Tumor Test May Predict Which Patients With HR-Positive Breast Cancer Will Benefit From Ovarian Suppression

Recent research sought to determine which patients with HR-positive breast cancer can benefit by adding ovarian function suppression to their adjuvant regimens, and which patients can skip it.

A tumor test reliably determined which premenopausal patients with HR-positive breast cancer would benefit by adding ovarian function suppression to their presurgical endocrine therapy, and which patients can skip ovarian suppression, which can come with short- and long-term side effects.

The Breast Cancer Index test showed that younger women with certain characteristics tended to benefit more from ovarian function suppression, according to findings from the SOFT trial, which were presented at the 2022 San Antonio Breast Cancer Symposium.

“This is the first genomic assay to demonstrate benefit from ovarian suppression, supporting additional clinical utility and value and validation of (Breast Cancer Index) and premenopausal women,” Dr. Ruth O’Regan, chair of medicine and Charles A. Dewey Professor at the University of Rochester, said in a presentation of the findings.

Younger Women Benefit More From Ovarian Suppression

The SOFT trial included 3,066 premenopausal women with HR-positive breast cancer. Patients were split up into three groups and randomly assigned to receive tamoxifen alone; tamoxifen plus ovarian function suppression; or exemestane plus ovarian function suppression, all for five years.

Data from that trial showed a 3% improvement in 12-year freedom from distant recurrence with exemestane plus ovarian function suppression compared with tamoxifen alone.

However, ovarian suppression can be toxic, and patients can struggle to continue taking the drugs. Therefore, it is crucial to identify which patients are most likely to benefit, O’Regan said.

Data from SOFT showed that women younger than 35 years appear to derive benefit from ovarian function suppression following chemotherapy.

Furthermore, investigators have developed a system that incorporates risk value age, nodal status, tumor size, grade, estrogen receptor (ER) status, progesterone receptor status, and Ki-67 that can assist with estimating the individual risk-based benefit of escalating endocrine therapy for HER2-negative patients.

“However, today, no genomic biomarker has been available to predict the benefit of errands of ovarian suppression premenopausal patients,” O’Regan said. “This is critical because of not just the short-term toxicities, but also long-term toxicities, which may not already be fully established.”

Seeking a Biomarker for Ovarian Suppression Benefit

To develop such a biomarker, O’Regan and her colleagues evaluated the predictive and prognostic ability of the Breast Cancer Index test in 1,711 patient tumor samples collected from the SOFT trial.

“(Breast Cancer Index) has been found to be prognostic in determining individualized risk of late recurrences and also cumulative overall distant recurrence from year zero to year 10,” O’Regan said.

The tool analyzes the ratio of two genes — HOXB13 and IL187BR, known as the (H/I) status —which previous studies showed can lend insight into the prognosis of patients with certain types of breast cancer.

The main goal of this study was to determine whether Breast Cancer Index (H/I) status was predictive for benefit with exemestane plus ovarian function suppression compared to tamoxifen. Investigators hypothesized that Breast Cancer Index (H/I)-high status would be predictive for ovarian suppression benefit, while BCI (H/I) low status would not.

In the data presented at SABCS, investigators assessed tumor samples collected from 573 patients assigned to tamoxifen, 551 assigned to tamoxifen plus ovarian suppression and 563 assigned to exemestane. The average follow-up was 12 years.

In the Breast Cancer Index analysis group of 1,687 patients, half (50.1%) of patients had grade 2 tumors, 25.4% had grade 1, 22.9% had grade 3, and tumor grade was unknown in 1.5%.

Patient age ranged from younger than 35 years (11.3%) to older than 50 years (10.6%). More than 65% of patients had no disease in their lymph nodes; 25.3% had disease in one to three of their lymph nodes; and 9.0% had disease in four or more lymph nodes. Tumor size was equal to or less than 2 cm in 64.1% of patients, greater than 2 cm in 34.4%, and was unknown in 1.5%.

For HER2 status, 11.7% of patients were positive. Most patients (53.3%) received chemotherapy. O’Regan said the Breast Cancer Index analysis cohort was representative of the parent SOFT trial.

Investigators determined that 58% of cancers were BCI (H/I) low and 42% were BCI (H/I) high. There was a significant treatment by biomarker interaction for exemestane plus ovarian function suppression compared to tamoxifen. The interaction was not as strong for tamoxifen plus ovarian suppression compared to tamoxifen alone.

Can (H/I) Status Predict Outcomes?

In the overall HR-positive cohort, those with (H/I)-high tumors, patients did not derive an absolute benefit for exemestane plus ovarian function suppression compared to or tamoxifen plus ovarian function suppression versus tamoxifen.

In contrast, investigators observed an absolute benefit of 11.6% for exemestane plus ovarian function suppression versus tamoxifen in the (H/I)-low group. For tamoxifen plus ovarian suppression versus tamoxifen, the absolute benefit was 7.3%.

In patients with HR-positive, HER2-negative tumors, BCI (H/I) was again predictive in the low group. The absolute 12-year benefit was 13.2% for exemestane plus ovarian suppression versus tamoxifen and 7.4% for tamoxifen plus ovarian function suppression versus tamoxifen.

In the BCI (H/I) group, the absolute benefit was –0.2% for exemestane plus ovarian function suppression compared to tamoxifen and –6.8% for tamoxifen plus ovarian function suppression versus tamoxifen.

Investigators also found that predictive performance 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 function suppression was smaller than the benefit derived from exemestane plus ovarian function suppression.

“BCI risk scores were prognostic in premenopausal women with HR-positive tumors receiving adjuvant endocrine therapy (with or without) chemotherapy in that higher BCI risk scores were associated with the worse outcome,” O’Regan said. “The BCI (H/I) was predictive of ovarian suppression benefit. However, contrary to our study hypothesis, the BCI (H/I)-low group consistently derived clinically meaningful benefit while the BCI (H/I)-high group did not. We’re not sure what these results mean, but it does point to potential differences in tumor biology underlying the ovarian suppression response.”

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