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SAN ANTONIO -- Among premenopausal women with hormone receptor (HR)-positive early-stage breast cancer, those with a low score on the Breast Cancer Index (BCI) genomic assay were more likely to benefit from the addition of ovarian function suppression (OFS) to primary adjuvant endocrine therapy, according to an analysis of the SOFT trial.

Among patients with low BCI HOXB13/IL17BR (H/I) status, those who received exemestane plus OFS had an absolute benefit of 11.6% versus tamoxifen alone (HR 0.48, 95% CI 0.33-0.71, P<0.01) at 12-year follow-up, while those who received tamoxifen plus OFS versus tamoxifen alone had an absolute benefit of 7.3% (HR 0.69, 95% CI 0.48-0.97, P=0.16), reported Ruth O'Regan, MD, of the University of Rochester Medical Center in New York, during the San Antonio Breast Cancer Symposium (SABCS).

On the other hand, patients with high BCI H/I status did not benefit from OFS, with 12-year absolute benefits of -0.4% in the exemestane plus OFS group versus the tamoxifen-alone group (HR 1.03, 95% CI 0.70-1.53), and -1.2% in the tamoxifen plus OFS group versus the tamoxifen-alone group (HR 1.05, 95% CI 0.72-1.54), O'Regan noted.

"This is the first genomic assay to demonstrate benefit from ovarian suppression, supporting additional clinical utility and validation of BCI in premenopausal women," she said.

The study also confirmed the prognostic value of the BCI, as women with higher risk scores were more likely to experience distant recurrence, O'Regan added.

In node-negative cancers, 61%, 22%, and 17% were BCI H/I-low, -intermediate, and -high, respectively. "BCI was highly prognostic in that as the score increased, the risk of distant recurrence also increased (P=0.0039) ... while patients with low scores have an improved outcome compared with patients with high scores," she said.

In the case of patients with N1 disease, 22% had BCIN+ low scores and 78% had BCIN+ high scores. "As the BCIN+ score goes up, so does the rate of distant recurrence (P=0.0094)," she explained. "And if you compare low versus high, patients with low scores do better than patients with high scores."

A 'Surprising Result'

Based on previous BCI data in adjuvant endocrine therapy, O'Regan and colleagues had actually hypothesized that BCI H/I-high status was predictive of OFS benefit, while low status indicated no OFS benefit.

However, they observed that the BCI H/I-low group consistently derived clinically meaningful benefit across all subgroups, while the BCI H/I-high group did not.

For example, when looking at patients with HR-positive/HER2-negative cancers, BCI-H/I was predictive in the low group, with a 13.2% benefit with exemestane plus OFS, and a 7.4% benefit with tamoxifen with OFS. However, BCI H/I was not predictive for either of the treatment arms in the high group.

This trend held regardless of age, receipt of prior chemotherapy, and lymph node status.

In commenting on this trend, SABCS discussant Polly Niravath, MD, of Houston Methodist Hospital in Texas, attempted to make sense "of a surprising result."

"In a clinical sense, we know that BCI H/I has been validated to predict tumors that benefit from extended endocrine therapy, because of endocrine responsiveness and late risk of recurrence," she said. "Using that information, we can then deduce that perhaps H/I-low tumors essentially have higher risk of early recurrence, so that augmented endocrine therapy in the first 5 years may be more effective for these tumors, whereas the H/I-high tumors -- because of their later risk of recurrence -- may not have as much of a benefit from early aggressive endocrine therapy."

"Perhaps these patients also need longer-term follow-up to reflect ultimate outcomes," she added.

The SOFT trial included 3,066 premenopausal women with HR-positive invasive early breast cancer, for whom endocrine therapy was escalated, specifically with the addition of OFS. A 12-year median follow-up demonstrated a 3% improvement in freedom from distant recurrence with exemestane plus OFS versus tamoxifen alone, as well as a greater benefit with exemestane plus OFS versus tamoxifen plus OFS.

"The problem is that ovarian suppression is associated with more toxicity, so we really want to try to identify which women need the addition of ovarian suppression," said O'Regan. "What we have found so far is that younger women under the age of 35 who receive chemotherapy appear to benefit from ovarian suppression, but unlike other ER-positive early-stage scenarios, there is no genomic biomarker to predict which patients need ovarian suppression."

The BCI incorporates molecular grade index and the H/I index ratio, and assesses the risk of late distant recurrence (5-10 years after diagnosis). The H/I ratio determines which patients benefit from extended durations of endocrine therapy.

This analysis included 1,687 patients -- 573 treated with tamoxifen alone, 551 with tamoxifen plus OFS, and 563 with exemestane plus OFS. More than half of the total population (53.3%) had received chemotherapy.

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