Extending adjuvant endocrine therapy beyond 5 years can reduce the risk of recurrence among patients with early-stage hormone receptor–positive breast cancer, but only a subset of patients derive benefit. There is a need for clinically validated biomarkers that can accurately assess an individual’s risk of long-term metastatic tumor recurrence and predict in which patients extended endocrine therapy may reduce the risk of recurrence.

Women with early-stage hormone receptor–positive breast cancer have a risk of distant tumor recurrence even years after completing their initial 5 years of adjuvant endocrine therapy, with a 10-year distant recurrence rate of up to 10%.1 More than 50% of all recurrences occur after the first 5 years of adjuvant endocrine therapy.2 Therefore, several clinical trials have been conducted to evaluate the potential benefits of extending adjuvant endocrine therapy beyond 5 years in reducing the risk of late recurrence.3-7 Although clinical studies have demonstrated that extending therapy can modestly reduce the risk of recurrence (1%–5% reduction in recurrence), only a subset of women derive benefit,3,4,6,8 and up to 50% of metastatic hormone receptor–positive breast tumors are inherently resistant to endocrine therapy.9 Additionally, many patients experience adverse events and impaired quality of life during extended endocrine therapy.3,4,6

Standard clinicopathologic factors, including tumor size, nodal status, and tumor grade, are commonly used to guide treatment decisions for patients with hormone receptor–positive breast cancer.10 Although these factors may prognosticate the risk of late recurrence in patients with hormone receptor–positive breast tumors,11-13 they are insufficient for accurately predicting clinical benefit from extended treatment.3,4,14-16 Therefore, many patients are overtreated or undertreated when extended endocrine decisions are solely based on standard clinicopathologic factors. There is a need for clinically validated biomarkers that can accurately assess an individual’s risk of long-term metastatic tumor recurrence and predict in which patients extended endocrine therapy may reduce the risk of recurrence. Such biomarkers can serve as valuable tools for guiding decisions regarding extended endocrine therapy.

One treatment strategy to reduce those late recurrences is to extend the duration of hormone-blocking treatment from 5 to 10 years. Preventing a late recurrence is saving a life. Rena Callahan, MD

“We know that about half of metastatic recurrences happen in the first 5 years after diagnosis, and half occur after that time point, many years later,” said Rena Callahan, MD, Associate Clinical Professor at UCLA David Geffen School of Medicine. “One treatment strategy to reduce those late recurrences is to extend the duration of hormone-blocking treatment from 5 to 10 years. Preventing a late recurrence is saving a life.”

Appropriate Biomarkers for Selecting Patients for Extended Endocrine Therapy

Multiple genomic assays are prognostic in patients with breast cancer, but few tests have been validated to predict benefit from extended endocrine therapy or chemotherapy in patients with early-stage hormone receptor–positive breast tumors.17-19 For a biomarker to be predictive, the effect of treatment must be different for biomarker-positive patients compared with biomarker-negative patients (Figure 1).19

Figure 1. Differences Between Predictive and Prognostic Biomarkers

Predictive (Benefit)

The effect/impact of therapy on patient’s risk
Before treatment selection
Identifies treatments likely to be effective and guides treatment decision making

Prognostic (Risk)

The patient’s overall outcome regardless of therapy (untreated or receiving standard therapy)
After diagnosis
Allows monitoring of disease status and recurrence

To determine whether a biomarker is potentially predictive or prognostic, a formal test for an interaction between the biomarker and the treatment group needs to be performed. A biomarker is considered predictive if the treatment impact (eg, benefit) is different for biomarker-positive patients vs biomarker-negative patients.

Adapted from Ballman et al19 and Louie et al.41

Commenting on the importance of predictive biomarkers in clinical decision-making, Joanne Mortimer, MD, Professor at City of Hope, noted, “Predictive information is most helpful at determining what treatments are likely to benefit a patient.”

Several genomic assays can be used at the time of diagnosis to inform treatment decisions. For example, a retrospective biomarker analysis of 774 postmenopausal women with estrogen receptor–positive, HER2-negative breast cancer showed that Oncotype DX recurrence score, Prosigna, Breast Cancer Index, EndoPredict, Clinical Treatment Score, and 4-marker immunohistochemical score provided prognostic information for overall recurrence (0–10 years); however, only the Breast Cancer Index® (BCI™) test, Prosigna, and EndoPredict maintained prognostic performance specifically in the late recurrence setting (5–10 years), the period in which an assay may be used to inform extended endocrine therapy decisions.1

For extended endocrine therapy planning, the ASCO® Clinical Practice Guidelines also identify several assays and biomarkers (Oncotype DX, EndoPredict, Prosigna, Ki67, IHC4) as having insufficient evidence to guide extended endocrine therapy decisions.20 In addition, a study evaluating the MammaPrint® 70-gene assay’s ability to predict extended endocrine therapy failed to meet its primary endpoint of distant recurrence.21 The BCI test is the only validated prognostic and predictive assay that is recognized by the ASCO® Clinical Practice Guidelines and the NCCN Clinical Practice Guidelines in Oncology® (NCCN Guidelines®) for use to predict extended endocrine therapy benefit for patients with early-stage hormone–positive breast cancer who have no evidence of recurrence after 5 years of primary endocrine therapy.20,22

“The decision to recommend extended endocrine therapy for patients with early-stage, hormone–positive breast cancer is relatively straightforward, as the BCI test is supported by both ASCO and NCCN Guidelines,” noted Dr. Mortimer. “It doesn’t make sense to check the BCI test at the initial diagnosis as some of these women will develop a recurrence prior to completing 5 years of endocrine therapy. Usually, we send tissue in year 4 of their endocrine therapy. So this means that you have to be mindful of how long a patient is on treatment and order the test.”

The Breast Cancer Index Genomic Assay

The BCI test is a gene expression–based test using the HOXB13/IL17BR ratio (H/I) and the molecular grade index (MGI; a set of five proliferative genes) to help guide the selection of patients for extended endocrine therapy.23,24 Six clinical trials involving over 4,500 patients with N0 and N1 disease (up to three positive nodes) have confirmed the ability of the BCI H/I ratio to predict benefit from extended endocrine therapy in patients with early-stage hormone receptor–positive breast cancer.24-29 Patients in these trials were administered various treatments (tamoxifen, aromatase inhibitors, or tamoxifen followed by an aromatase inhibitor). Across these studies, BCI H/I–high was consistently associated with benefit from extended endocrine therapy (58%–67% relative risk reduction), and BCI H/I–low patients consistently derived no significant benefit from extended endocrine therapy.24-27,29

“The BCI test helps us to distinguish which patients with early-stage hormone receptor–positive breast cancer are going to benefit from 10 years of adjuvant endocrine therapy and which patients will not benefit,” said Dr. Mortimer.

The BCI test helps us to distinguish which patients with early-stage hormone receptor–positive breast cancer are going to benefit from 10 years of adjuvant endocrine therapy and which patients will not benefit. Joanne Mortimer, MD

Shifting Extended Endocrine Therapy Assumptions Made Based on Clinicopathologic Factors

Studies have shown that the combination of MGI and the H/I ratio is also prognostic, allowing for risk stratification based on late distant recurrence (5–10 years after diagnosis).29-33 The TEAM trial represents the largest prognostic validation study for the BCI test. In this study, the BCI test significantly predicted 10-year recurrence in 3,544 patients with early-stage hormone–positive breast cancer.33,34 The prognostic value of the BCI test was validated for both node-negative and node-positive disease. In another analysis, one of four patients with T1N0 disease (seemingly low risk) were identified by the BCI test as being at high risk of late distant recurrence and likely to reduce recurrence with extended endocrine therapy.32 These results demonstrate the ability of the BCI test to identify seemingly low-risk patients who are at an elevated risk of recurrence to help prevent a potentially life-threatening metastatic recurrence. Moreover, one out of five patients with N1 tumors (typically considered high risk and recommended to receive extended endocrine therapy) were identified by the BCI test as having a low risk of late recurrence,31,33 suggesting that implementing the BCI test could spare women’s exposure to side effects and toxicities of longer treatment.

Implementation of the BCI Test Changed Extended Endocrine Decisions for 40% of Patients

A multicenter prospective study of patients with stage I to III hormone receptor–positive breast cancer enrolled in the BCI Registry Study assessed the real-world clinical impact of incorporating the BCI test results into extended endocrine therapy decision-making.35 The patients had finished their initial 4 to 7 years of adjuvant endocrine therapy and were considering whether to extend treatment. Initial results from the first 1,073 patients enrolled demonstrated that physician treatment recommendations regarding extended endocrine therapy changed in 338 of 843 (40.1%) patients based on completed physician questionnaires following the BCI test results (P < .0001; Figure 2), suggesting a significant group of patients may potentially be overtreated or undertreated without the BCI test.35

In 63.3% (214 of 338) of patients, physicians opted not to recommend extended endocrine therapy after initially planning to recommend it.35 This change in clinical decision-making could prevent overtreatment and spare unnecessary toxicities from extended treatment in patients who are unlikely to benefit. In the remaining 36.7% (124 of 338) of changes in decision-making, the physician recommendation changed from “no extended endocrine therapy” to “yes extended endocrine therapy.”35

Figure 2. Physician Recommendation for Extended Endocrine Therapy Before and After BCI Testing

Adapted from Sanft et al.35
BCI = Breast Cancer Index; EET = extended endocrine therapy.

“Uptake of new treatments often takes a while to be embraced by clinicians,” observed Dr. Mortimer, noting that she was hopeful that adoption of this tool would continue to improve after its inclusion in the ASCO® Clinical Practice Guideline and the NCCN Guidelines. “There are ‘enhancements’ being made in the electronic record to help busy clinicians recognize the benefits of the test and facilitate ordering the test,” she added.

Impact of BCI Test Adoption on Physician Confidence and Patient Comfort

Another key finding of the BCI Registry Study was that 38.8% (n = 327) of physicians reported feeling more confident in their decision-making after receiving the BCI test results (P < .0001).35 The proportion of physicians who felt confident increased from 58.2% (n = 490) before BCI testing to 80.5% (n = 679) after BCI testing (Figure 3). Conversely, the proportion of physicians with low confidence levels decreased from 39.1% (n = 330) to 18.8% (n = 158) before and after testing, respectively.

Figure 3. Physician Confidence Levels and Patient Comfort Levels Regarding Extended Endocrine Therapy Before and After BCI Testing

aLow-confidence group comprises physicians who reported being “not at all confident,” “not confident,” or “ambivalent” before or after BCI testing.
bHigh-confidence group comprises physicians who reported being “confident” or “strongly confident” before or after BCI testing.
cLow-comfort group comprises patients who reported being “not at all comfortable,” “not comfortable,” or “ambivalent” before or after BCI testing.
dHigh-comfort group comprises patients who reported being “comfortable” or “strongly comfortable” before or after BCI testing.
Adapted from Sanft et al.35
BCI = Breast Cancer Index; EET = extended endocrine therapy.

The study also demonstrated the favorable impact of BCI test adoption on shared decision-making. Patient questionnaires were used to assess patients’ perspectives on the impact of the BCI test adoption on their treatment.34 After receiving their BCI test results, 341 of 823 (41.4%) patients who completed pre-BCI and post-BCI questionnaires felt more comfortable with their treatment decision regarding extended therapy (P < .0001; Figure 3).35 After receiving their BCI test results, 371 of 823 (45.1%) patients changed their preferences regarding extended endocrine therapy.35 Changes in patient preference following BCI testing aligned with their BCI test results and their doctor's updated recommendation; when BCI test results indicated a high likelihood of benefit, both doctors and patients favored extending therapy.

“As physicians, we make treatment recommendations based on our knowledge and clinical experience. Patients are the ultimate decision-makers,” noted Dr. Callahan. “They are the ones who have to take these pills daily and experience the side effects. So, we need their buy-in to a proposed treatment plan for it to have any impact.”

As physicians, we make treatment recommendations based on our knowledge and clinical experience. Patients are the ultimate decision-makers. They are the ones who have to take these pills daily and experience the side effects. So, we need their buy-in to a proposed treatment plan for it to have any impact. Rena Callahan, MD

Furthermore, the percentages of patients with concerns about cost (20.9%; P = .0001), safety (25.4%; P = .0014), and perceived lack of benefit from extending therapy (29.3%; P = .0002) were significantly reduced after testing.35 In a separate decision impact study conducted at Yale University School of Medicine and University of Pittsburgh Medical Center, 82% of patients recommended for extended endocrine therapy stated they would be more likely to be compliant based on the BCI test results.36

“Five years is a long time, and these concerns are voiced by patients every day in clinical practice. So when we recommend another 5 years of treatment, we may be met with some opposition,” acknowledged Dr. Callahan. “This tool contextualizes our recommendations to extend endocrine therapy. A patient can see when the benefits outweigh the risks.”

Oncotype DX Breast Recurrence Score

Oncotype DX Breast Recurrence Score is a 21-gene assay that has been developed to guide treatment decisions by prognosticating the risk of recurrence in patients with early-stage hormone receptor–positive, HER2-negative breast cancer.37,38 The Oncotype DX test was validated primarily for predictions of distant recurrence within the initial 5 years after diagnosis and for identifying patients who are likely to benefit from addition of adjuvant chemotherapy to endocrine therapy.37,38 However, there is insufficient evidence from prospective clinical studies to support the utility of Oncotype DX Breast Recurrence Score in guiding endocrine therapy decisions.20 In addition, the benefit of extended endocrine therapy may not always correlate with the level of recurrence risk.39

Data presented at the 2024 ASCO Annual Meeting showed that in 847 patients with early-stage hormone–positive breast cancer in the BCI Registry Study, the Oncotype DX Breast Recurrence Score exhibited low concordance with the BCI test. In contrast to the Oncotype DX Breast Recurrence Score, the BCI test consistently restratified patients based on benefit from extended endocrine therapy.40 In addition, the study found that 30.8% of patients aged > 50 years who were identified as unlikely to benefit from chemotherapy based on Oncotype DX results were reclassified as likely to benefit from extended endocrine therapy based on the BCI test results. Furthermore, 38.6% of patients aged > 50 years who were identified as likely to benefit from chemotherapy based on Oncotype DX results were reclassified as unlikely to benefit from extended endocrine therapy based on the BCI test results. These findings suggest that many patients may be over- or undertreated if extended endocrine therapy decisions are based on Oncotype DX results alone, and that using a test that predicts chemotherapy benefit may lead to inappropriate extended endocrine therapy decisions.

Conclusions and Future Directions

Extended endocrine therapy decisions are complex, and incorporating genomic testing may help standardize decision-making. Findings of the real-world clinical impact of the BCI test adoption from the first results of the prospective BCI Registry Study demonstrate the potential impact genomic testing may have on standardizing treatment decisions. Given the findings were based on self-reported questionnaires from physicians and patients, ongoing study follow-up will help validate aspects such as medication adherence.

Future studies are needed to explore and expand the application of genomic assays, such as the BCI test, across diverse patient populations and treatment scenarios. Prospective studies should aim to validate and potentially broaden the clinical utility of the BCI test and other genomic assays across the continuum of care, including the neoadjuvant, adjuvant, and extended endocrine therapy settings. These studies should include both postmenopausal and premenopausal women with early-stage breast cancer to ensure that the benefits of genomic assays are accessible to all patients, regardless of menopausal status.

Commenting on overcoming challenges in the BCI test's clinical adoption, Dr. Callahan said: “Genomic assays can be costly to a patient. We need to continue to accumulate data so there is better payor coverage. We also need to increase awareness amongst physicians of the utility of genomic tools.”

Disclosure

Dr. Callahan has served in a consulting or advisory role with Gilead, Pfizer, AstraZeneca, Daiichi Sankyo, Lilly, Novartis, and Biotheranostics, Inc, A Hologic Company.

Dr. Mortimer has served in a consulting or advisory role with Puma, GlaxoSmithKline, Pfizer, and Novartis.

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