The recommended duration of adjuvant endocrine therapy for patients with hormone receptor–positive early breast cancer ranges from 5 to 10 years. However, determining the optimal agent and duration of endocrine therapy in the extended setting has become increasingly complex.

Adjuvant endocrine therapy is the cornerstone of systemic treatment for women with hormone receptor–positive breast cancer. The recommended duration of adjuvant endocrine therapy for patients with hormone receptor–positive early breast cancer ranges from 5 to 10 years; however, determining the optimal agent and duration of endocrine therapy in the extended setting has become increasingly complex.1

Balancing the probability of disease recurrence with the potential risk of side effects from treatment when considering therapy beyond 5 years can be challenging. For women who complete 5 years of endocrine therapy, the risk of relapse continues for up to 20 years or more from diagnosis, but extended adjuvant treatment is associated with increased cardiovascular risk, bone fractures, and side effects that impair quality of life and decrease compliance.2,3

Historically, the decision to offer extended therapy beyond 5 years to patients with early-stage breast cancer has been based on clinical and pathologic factors to determine recurrence risk.4 The development of predictive biomarkers has improved the ability to identify the subset of patients who are likely to benefit from more than 5 years of endocrine therapy.5-8

Risk of Recurrence Continues Beyond 5 Years of Adjuvant Endocrine Therapy

For patients with early-stage, hormone receptor–positive breast cancer, more than half of recurrences occur beyond 5 years of primary treatment.9 In fact, a large meta-analysis revealed that after 5 years of endocrine therapy, a persistent risk of recurrence and death continues for at least 20 years beyond original diagnosis.3 This study of 66,000 women from 88 trials provided significant insight into the risk of late recurrence after 5 years of adjuvant endocrine therapy based on traditional clinicopathologic features, identified as tumor size, grade, and nodal (TN) status.

Even low-grade T1N0 disease carries an appreciable risk of distant recurrence and contralateral breast cancer—the absolute risk of distant recurrence among this group was 4% at 10 years, reaching a 15-year cumulative recurrence rate of 13%—sufficient for at least the consideration of extended endocrine therapy. Another recent meta-analysis also found a discernible rate of late distant recurrence in patients treated with 5 years of endocrine therapy based on clinicopathologic risk factors: a 5.4% cumulative risk for years 5 to 14 for women with T1N0 low-grade disease.10 However, patients with early-stage, hormone receptor–positive breast cancer with “favorable” clinicopathologic features are often not recommended for extended endocrine therapy.

Conversely, having high-risk clinicopathologic features does not always correlate with responding to a particular therapy, likely because these prognostic features fail to distinguish the biologic heterogeneity of tumors.6,7,11-13 “In the past, we extended therapy based solely on clinicopathologic factors, such as tumor size and nodal status,” explained Reshma Mahtani, DO, Associate Professor of Clinical Medicine at the University of Miami, Co-Leader of the Breast Cancer Program, and Director of Community Outreach at Sylvester Comprehensive Cancer Center, Deerfield Beach, Florida. “This information is certainly prognostic, but clinicopathologic features do not reliably predict who will—or will not—benefit from extended endocrine therapy.” Further stratification of risk for late distant recurrence and likelihood of benefiting from extended endocrine therapy is ideal for better facilitation of individualized treatment planning.

[Clinicopathologic features are] certainly prognostic, but [they] do not reliably predict who will—or will not—benefit from extended endocrine therapy Reshma Mahtani, DO

Importance of Understanding Which Patients May Have Preferential Benefit

Identifying women whose tumors are likely to respond to endocrine therapy is key to avoiding unnecessary suffering from the significant side effects associated with this treatment.14 “Many patients face challenges with endocrine agents including arthralgias, bone loss, sexual dysfunction, cognitive impairment, and increased risks of endometrial cancer and thrombosis,” said Dr. Mahtani. “Although a 3% to 5% absolute benefit in preventing recurrences is consistently seen with additional endocrine therapy beyond 5 years, some patients do not benefit and are only suffering the toxicities of treatment.”

Not surprisingly, the considerable side effects associated with endocrine therapy often drive serious issues with adherence and negatively affect quality of life (Figure 1).6,15 The reported discontinuation rates of adjuvant endocrine therapy vary widely, from 8% to 28% in clinical trials up to 31% to 73% in clinical practice settings.16

Figure 1. Patient Reasons for Discontinuation of Extended Endocrine Therapy17

Poor adherence further erodes the already modest benefit from extended endocrine therapy. In a study of almost 9,000 women receiving adjuvant hormone therapy, 31% of patients discontinued therapy early; of those who continued therapy, an additional 28% were nonadherent.18 The estimated survival at 10 years was significantly lower for women who discontinued treatment: 73.6% vs 80.7% for those who continued therapy (P < .001). The estimated 10-year survival was also significantly lower for those who continued therapy but were nonadherent.

Prognostic Biomarkers vs Predictive Biomarkers: Guiding Treatment Decisions

In the past 2 decades, several multiparameter genomic tests have been developed to guide the care of patients with early breast cancer.19-22 “Genomic assays provide a more in-depth understanding of the biology of an individual’s tumor by looking at various levels of gene expression,” explained Dr. Mahtani. All of the commercially available tests include prognostic biomarkers, which provide information about the patient’s overall cancer outcome, regardless of therapy.23

A biomarker is predictive if a treatment causes a different effect in patients who are biomarker-positive compared with patients who are biomarker-negative (Figure 2).23 One example of a predictive biomarker test is the 21-gene recurrence score, which is designed to predict if women diagnosed with early-stage, hormone receptor–positive, HER2-negative breast cancer will respond to chemotherapy.

Figure 2. Prognostic vs Predictive Features

Abbreviations: H/I = HOXB13:IL17BR; MGI = molecular grade index.

Predictive Biomarker for Extended Endocrine Therapy

Another gene expression-based biomarker test, the algorithmic combination of the HOXB13:IL17BR (H/I) gene expression ratio and molecular grade index (MGI), is both a predictive and prognostic assay for extended endocrine therapy benefit. “The ratio of the two genes HOXB13 and IL17BR essentially provides a molecular assessment of the estrogen signaling pathway,” said Dr. Mahtani. The H/I ratio alone informs responsiveness to endocrine therapy—a predictive biomarker—and the combination of both H/I ratio and MGI provides information about outcome and serves as a prognostic tool.24

The H/I ratio is recognized by the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Breast Cancer for the prediction of benefit from extended endocrine therapy beyond 5 years.1 “The H/I ratio has the unique distinction of being the only genomic assay that provides predictive information on extended endocrine therapy benefit,” said Dr. Mahtani. Added V.K. Gadi, MD, PhD, Professor and Director of Medical Oncology in the Department of Medicine and Associate Director of Translational Oncology at the University of Illinois at Chicago Cancer Center, “I was an early adopter of this test, but it gives me even more confidence that it is now part of the NCCN Guidelines and has been recognized by a panel of like-minded individuals.”

The H/I ratio and MGI biomarkers were originally trained using a cohort of tamoxifen-treated patients from the randomized, prospective Stockholm trial. In this study, the combination of both biomarkers demonstrated a prognostic ability to provide an individual risk of distant breast cancer recurrence based on a continuous risk model.24

Multiple studies have confirmed the ability of the H/I ratio to predict benefit for primary and extended endocrine therapy, including the MA.17 trial, Trans-aTTom trial, and IDEAL study.7,19,25-27 “We now have extensive clinical evidence of the test validity and utility in both node-negative and node-positive patients, and across antiestrogen therapies including tamoxifen and aromatase inhibitors,” explained Dr. Mahtani. Dr. Gadi agreed that the considerable available data are reassuring: “The consistency of the results globally across independent studies and different populations emboldens my confidence in the reliability of the H/I ratio. We now have data that fill in our gaps in knowledge.”

We now have extensive clinical evidence of the test validity and utility in both node-negative and node-positive patients, and across antiestrogen therapies including tamoxifen and aromatase inhibitors. Reshma Mahtani, DO

In recent data released from a translational study of the IDEAL trial, women with a high H/I ratio experienced a 58% and 66% reduction in relative risk of recurrence in the overall cohort (N = 908) and in the subset treated with primary adjuvant aromatase inhibitors (N = 794), respectively, whereas those with a low H/I ratio did not show benefit from extended endocrine therapy.19 The study also reinforced through subset analyses that the H/I ratio’s ability to predict benefit of extended endocrine therapy was independent of clinicopathologic variables—approximately 50% of patients with clinically high-risk disease did not benefit from extended therapy. Additionally, the authors found that only 7.5 years of endocrine therapy vs 10 years is not sufficient for patients who have a high H/I index. “Notably, this trial provided us with valuable information about patients who were treated with 10 years of an aromatase inhibitor, which is becoming increasingly common in clinical practice,” said Dr. Mahtani.

At the 2021 ASCO Annual Meeting, the H/I biomarker was validated in the NSABP B-42 study, demonstrating consistent evidence with previous studies.28 In the time-dependent distant recurrence analysis, patients who had a high H/I index showed a statistically significant benefit from extended letrozole therapy after 4 years. In addition, the prediction of extended treatment benefit by H/I ratio was more apparent in the HER2-negative subset.

Although extensive clinical evidence is now available to guide treatment decisions, Dr. Gadi noted that some holes in the data exist. “We still need to see if really young women stand to benefit from extended endocrine therapy. Hopefully these data will be available to us in the future.”

Prognostic Value of Biomarker Assay

The combination of MGI and the H/I index also holds prognostic value, separate from the predictive ability of the assay, to identify patients who may be overtreated or undertreated based on their risk profile determined solely by clinicopathologic features. The prognostic assay has been validated in both node-negative and node-positive patients.

The assay demonstrated “significant, sustainable” prognostic performance that spans from the time of diagnosis to 10 years after diagnosis for the prediction of individual risk of distant recurrence for patients with hormone receptor–positive, lymph node–negative disease treated with tamoxifen.25,29 For node-positive patients, the integrated assay—combining H/I index, MGI, and tumor size and grade—identified 20% of node-positive patients with limited risk of recurrence over 15 years, in whom extended endocrine treatment could be spared.30

Conversely, the prognostic assay also identified a significant subset population (> 30%) of clinically low-risk women who were at a significantly higher genomic risk of late distant recurrence that would not have been identified using clinicopathologic data alone.31

Interpreting Assay Results

The predictive results are provided in a simple “Yes/No” format. Patients with a low H/I ratio—a “No” predictive result on the clinical test report—do not derive any recurrence-prevention benefit from a longer duration of endocrine therapy, while a high H/I ratio—a “Yes” on the report—is associated with an approximately 58% to 71% risk reduction by continuing endocrine therapy to 10 years.7,27 “An advantage to this assay is that the information is provided as a dichotomous result, which makes communicating the information to the patient straightforward,” said Dr. Gadi. “It can really help tailor your conversation, in terms of how to articulate the next steps in therapy. Patients have indicated that they are more likely to be compliant with the decision based on the H/I ratio.”

An advantage to this assay is that the information is provided as a dichotomous result, which makes communicating the information to the patient straightforward. V.K. Gadi, MD, PhD

The second portion of the clinical report is the prognostic result, which is expressed as a percentage indicating the risk of late distant recurrence for women who completed the first 5 years of endocrine therapy. For women with lymph node–positive disease, genomic risk is calculated by integrating tumor size and grade with the H/I ratio and MGI.

Testing Patients

Extensive clinical evidence indicates that the H/I index biomarker assay holds value, but which patients stand to benefit from the information provided? “I will consider any patient with hormone receptor–positive, early-stage disease—meaning patients with fewer than three lymph nodes,” explained Dr. Gadi. “For patients with more nodes, we just do not have the data.”

Dr. Mahtani emphasized that the results of the assay are sometimes unexpected. “I have been really surprised to see the assumptions we make using clinicopathologic features alone be challenged by the results of the H/I ratio,” she said. “The results have motivated some of my patients to continue therapy, while sparing others the toxicity when they were found to have a low risk of recurrence and no benefit to continuing treatment.”

Cost Savings

There is evidence that incorporating the H/I ratio into clinical practice may have a beneficial financial impact in the management of early-stage breast cancer. A prospective decision-impact study revealed that the assay meaningfully impacted physician recommendations regarding endocrine therapy beyond 5 years and decreased patient decision conflict—with projected cost savings.32 Interestingly, the assay results led to a change in physician treatment recommendation for 30% of patients; in 71% of these cases, this change was from “recommend extended therapy” to “do not recommend extended therapy.”

Balancing Knowledge With Caution in Patient Care

Dr. Mahtani emphasized the “critical importance” of managing toxicities associated with endocrine therapy. “While it’s great that this tool has spared some women exposure to more endocrine therapy, we need to do a better job helping women that really benefit from treatment to manage the common side effects that ultimately impact quality of life.”


The introduction of predictive biomarkers has allowed oncologists to optimize medical care by tailoring the treatment of patients based on their tumor’s genetic and molecular characteristics. “We have moved into an era of precision medicine,” concluded Dr. Mahtani. “The availability of genomic assays has really allowed us to adapt our treatments and spare toxicities for those who will not benefit.” Predictive genomic testing will continue to stratify patients for personalized therapy in the future, increasing patient and physician confidence in the valuable information that these assays provide.


V.K. Gadi, MD, PhD, has served in a leadership role with SEngine Precision Medicine; owns stock and/or other interests with SEngine Precision Medicine, Novilla, 3rdEyeBio, New Equilibrium Biosciences, and Phoenix Molecular Designs; has served in a consulting or advisory role with Seattle Genetics, Puma Biotechnology, Novartis, and Sanofi; has served on a speakers’ bureau with Seagen, Roche, Puma, and Biotheranostics; has received research funding from Genentech/Roche, Agendia, and SignalOne Bio; and has received travel, accommodations, or expenses from Novartis.

Reshma Mahtani, DO, has served in a consulting or advisory role with Agendia, Amgen, AstraZeneca, Biotheranostics, Daaichi, Eisai, Genentech, Immunomedics/Gilead, Lilly, Merck, Novartis, Pfizer, Puma Biotechnology, Sanofi, and Seattle Genetics; has received research funding from Genentech; and has received travel, accommodations, or expenses from Agendia, Amgen, AstraZeneca, Biotheranostics, Daiichi Sankyo/Lilly, Eisai, Genentech/Roche, Lilly, Merck, Novartis, Pfizer, Puma, Sanofi, and Seattle Genetics.


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