In an analysis of the SOFT trial, the Breast Cancer Index accurately identified premenopausal women with hormone receptor–positive early breast cancer who may benefit from ovarian function suppression in addition to adjuvant endocrine therapy. The findings were reported by Ruth O’Regan, MD, Chair of Medicine and the Charles A. Dewey Professor at the University of Rochester, New York, at the 2022 San Antonio Breast Cancer Symposium.¹

“BCI was highly prognostic for distant recurrence in premenopausal women with hormone receptor–positive, node-negative cancers.”

— Ruth O’Regan, MD

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“The Breast Cancer Index (BCI) is the first genomic assay to demonstrate benefit from ovarian suppression, supporting the additional clinical utility of this test in premenopausal women,” Dr. O’Regan said. “What we found, first of all, is that the BCI was prognostic in patients with either node-negative or node-positive disease. As the BCI [score] went up, the rate of distant recurrence also went up. The second thing we found was that low BCI (HOXB13/IL-17BR [H/I], a two-gene ratio measuring estrogen signaling) was predictive for benefit from ovarian suppression. In that group, patients who received exemestane plus ovarian suppression did much better than women who got tamoxifen without ovarian suppression. Likewise, if they got tamoxifen plus ovarian suppression, they did better than with tamoxifen alone,” she reported.

Need to Predict Benefit of
Ovarian Suppression

SOFT, a landmark international nonblinded, randomized clinical trial, included 3,047 premenopausal women with hormone receptor–positive breast cancer. Patients were randomly assigned to receive 5 years of tamoxifen alone, tamoxifen plus ovarian suppression, or exemestane plus ovarian suppression. The latest analysis showed a 3% absolute improvement in 12-year distant recurrence–free survival with exemestane plus ovarian suppression compared with tamoxifen alone (hazard ratio [HR] = 0.75; 95% confidence interval [CI] = 0.59–0.97).²

“The problem is that we still don’t really know which premenopausal patients need that approach…. This is critical because ovarian suppression is associated with both short-term and probably not fully realized long-term toxicities…. Additionally, some patients may stop taking their endocrine therapy altogether because of some of these side effects, so it’s important to determine which patients are most likely to benefit from ovarian suppression,” she said.

So far, the investigators have shown a benefit in women younger than age 35. In addition, they have developed a continuous composite that incorporates age, nodal status, tumor size and grade, estrogen receptor status, progesterone receptor status, and Ki67 index that can help estimate the individual risk-based benefit of escalating endocrine therapy for patients with HER2-negative disease. No genomic biomarker, however, has been able to predict for benefit and help select those patients truly needing ovarian suppression.

Information From the Breast Cancer Index

Dr. O’Regan and her colleagues evaluated the predictive and prognostic ability of the BCI as such a biomarker. The BCI is a genomic assay that assesses the risk of late distant recurrence (5–10 years) and cumulative overall distant recurrence (0–10 years) in hormone receptor–positive early breast cancer. For use in patients with node-negative disease, the BCI incorporates molecular grade index (five genes related to tumor grade and proliferation) and the H/I index ratio. Patients with a high H/I ratio benefit from a longer duration of endocrine therapy, and those with low scores do not. In patients with node-positive disease, the BCI node-positive (BCIN+) assay further incorporates tumor size and grade.

Two hypotheses were tested in the SOFT population, in whom 58% of cancers were BCI (H/I)–low and 42% were BCI (H/I)–high:

BCI and BCIN+ are prognostic in node-negative and node-positive disease, respectively, in patients who receive endocrine therapy with or without chemotherapy.

BCI (H/I) status predicts for benefit of ovarian suppression, whereas BCI (H/I)–low status predicts for lack of benefit.

The study endpoints were breast cancer–free interval for the predictive analysis and distant recurrence–free interval for the prognostic analysis.

Researchers applied the BCI to 1,717 patient tumor samples collected in the SOFT trial; this analysis cohort was representative of the parent trial. About 12% of patients had HER2-positive breast cancers, and 53.3% received chemotherapy in addition to endocrine therapy. Median follow-up was 12 years.

Prognostic Ability of BCI

“BCI was highly prognostic for distant recurrence in premenopausal women with hormone receptor–positive, node-negative cancers. As the score increased, the risk also increased. Patients with low scores had an improved outcome over patients with high scores,” Dr. O’Regan said.

In patients with node-positive disease, the investigators observed a similar result: higher BCIN+ scores were associated with a greater risk of distant recurrence, and patients with low scores fared better than patients with high scores. This finding was highly correlated with grade, in that patients with lower scores predominantly had low-grade cancers and those with high scores had grade 2 or 3 cancers.

Predictive Ability of BCI

The researchers further observed a significant treatment-by-biomarker interaction for exemestane plus ovarian suppression vs tamoxifen (P < .01) but a weaker interaction for tamoxifen plus ovarian suppression vs tamoxifen (P = .16). “But, in contrast to our hypothesis, we found that in the BCI (H/I)–high group, this was not predictive of benefit; there was no difference between the arms at all,” she said.

The absolute benefit in the BCI (H/I)–high group, in fact, was negative: –0.4% with exemestane plus ovarian suppression vs tamoxifen (HR = 1.03; 95% CI = 0.70–1.53) and –1.2% with tamoxifen plus ovarian suppression vs tamoxifen (HR = 1.05; 95% CI = 0.72–1.54). In contrast, in the BCI (H/I)–low group, the absolute benefits for these treatments vs tamoxifen alone were 11.6% (HR = 0.48; 95% CI = 0.33–0.71) and 7.3% (HR = 0.69; 95% CI = 0.48–0.97), respectively, Dr. O’Regan reported.

In patients with hormone receptor–positive, HER2-negative tumors—a subset that eliminated the 12% of patients with HER2-positive tumors—the results were essentially identical. And the predictive performance of BCI was generally consistent across subgroups, including nodal status, prior chemotherapy, and age. Furthermore, consistent with data reported from the SOFT trial, the benefit derived from tamoxifen plus ovarian suppression was smaller than the benefit derived from exemestane plus ovarian suppression.

Summing Up

Summing up findings, Dr. O’Regan said: “BCI risk scores were prognostic in premenopausal women with hormone receptor–positive tumors receiving adjuvant endocrine therapy with or without chemotherapy, in that higher BCI risk scores were associated with the worse outcome. The BCI (H/I) ratio was predictive of ovarian suppression benefit, but contrary to our study hypothesis, the BCI (H/I)–low group were the patients who derived clinically meaningful benefit, whereas the BCI (H/I)–high group did not. These results point to potential differences in the tumor biology underlying ovarian suppression response.”

Dr. O’Regan added that if the results are validated, clinicians could have “a new tool for evaluating premenopausal patients in the clinic, to determine what is the right endocrine therapy approach…. I think this is very exciting, and we look forward to future data.” 

DISCLOSURE: Dr. O’Regan has served as an advisor to Biotheranostics, Novartis, AstraZeneca, and Pfizer.

REFERENCES

1. O’Regan R, Zhang Y, Fleming GF, et al: Evaluation of the Breast Cancer Index in premenopausal women with early-stage HR+ breast cancer in the SOFT trial. 2022 San Antonio Breast Cancer Symposium. Abstract GS1-06. Presented December 6, 2022.

2. Francis PA, Fleming GF, Lang I, et al: Adjuvant endocrine therapy in premenopausal breast cancer: 12-year results from SOFT. J Clin Oncol. December 9, 2022 (early release online).