Highlight
– BCI (H/I) remains a validated prognostic marker in premenopausal hormone receptor–positive breast cancer, with graded 12‑year distant recurrence risk across BCI-defined strata.
– In SOFT, BCI(H/I)-low tumors derived clear benefit from OFS-containing regimens relative to tamoxifen alone; in TEXT the BCI(H/I) status did not convincingly predict a larger advantage of exemestane+OFS over tamoxifen+OFS.
– Clinical interpretation: BCI can inform prognosis for premenopausal patients and may help identify those likely to benefit from adding OFS to tamoxifen, but it is not a definitive arbiter for choosing exemestane+OFS over tamoxifen+OFS.
Background and clinical context
Premenopausal women with early-stage hormone receptor–positive (HR+) breast cancer face decisions about adjuvant endocrine therapy that balance recurrence risk reduction against substantial treatment-related effects. The addition of ovarian function suppression (OFS) to endocrine therapy improves outcomes for higher-risk premenopausal patients but increases menopausal symptoms, sexual dysfunction, bone loss, and quality‑of‑life burdens. A validated genomic biomarker that both prognosticates distant recurrence risk and predicts who will derive incremental benefit from OFS-based intensification would therefore be clinically valuable.
The Breast Cancer Index (BCI) is a genomic classifier that incorporates the HOXB13/IL17BR ratio (H/I) and a proliferation-related molecular grade index. Prior work suggested that the H/I component may identify tumors whose biology predicts different sensitivity to endocrine strategies. Two recent prospective‑retrospective translational analyses of TEXT and SOFT trial specimens aimed to clarify BCI’s prognostic and predictive performance among premenopausal patients randomized within these trials.
Study designs and analytic aims
Both analyses used a prospective‑retrospective approach: BCI testing was performed on archived tumor specimens blinded to clinical data and outcomes, then linked to the parent randomized trials.
Key studies:
- SOFT cohort (JAMA Oncology 2024): Evaluated BCI in premenopausal patients randomized to tamoxifen alone, tamoxifen+OFS, or exemestane+OFS. Primary predictive hypothesis: BCI(H/I)-high tumors would derive greater benefit from OFS (and specifically OFS-containing regimens) vs tamoxifen alone; BCI was also tested prognostically for distant recurrence-free interval (DRFI).
- TEXT cohort and combined TEXT+SOFT analysis (JAMA Network Open 2025): Focused on the comparative benefit of exemestane+OFS vs tamoxifen+OFS, with BCI(H/I) as a candidate predictive biomarker; prognostic performance for DRFI was also reassessed.
Primary endpoints: breast cancer–free interval (BCFI) for predictive analyses and distant recurrence–free interval (DRFI) for prognostic analyses. Median follow-up exceeded a decade in both cohorts (≈12–13 years), enabling evaluation of long-term outcomes.
Key results — predictive performance
SOFT (comparing OFS-containing regimens to tamoxifen alone):
– Among 1,687 patients with evaluable BCI, 57.6% were BCI(H/I)-low and 42.4% were BCI(H/I)-high. Patients with BCI(H/I)-low tumors experienced substantial absolute improvement in 12‑year BCFI from exemestane+OFS (11.6%; HR 0.48; 95% CI, 0.33–0.71) and a smaller but significant benefit from tamoxifen+OFS (7.3%; HR 0.69; 95% CI, 0.48–0.97) compared with tamoxifen alone. By contrast, patients with BCI(H/I)-high tumors did not benefit from OFS-containing regimens versus tamoxifen alone (exemestane+OFS: absolute benefit −0.4%; HR 1.03; 95% CI, 0.70–1.53; P for interaction = .006 for the comparison with exemestane+OFS).
TEXT (comparative: exemestane+OFS vs tamoxifen+OFS):
– In TEXT, 1,782 patients were analyzed (BCI(H/I)-low in 58.0%). For BCI(H/I)-low tumors, exemestane+OFS conferred a 6.6% absolute improvement in 12‑year BCFI versus tamoxifen+OFS (HR 0.61; 95% CI, 0.44–0.85). For BCI(H/I)-high tumors the absolute benefit was 6.3% (HR 0.78; 95% CI, 0.57–1.07). The interaction test for treatment×BCI(H/I) was not statistically significant (P = .29), indicating that BCI(H/I) did not clearly predict a differential benefit of exemestane+OFS compared with tamoxifen+OFS.
Combined TEXT+SOFT analyses and subgroup-adjusted models produced broadly consistent findings: BCI(H/I)-low status identified patients who benefit from adding OFS to tamoxifen (SOFT), whereas BCI(H/I) did not robustly discriminate between exemestane+OFS and tamoxifen+OFS (TEXT).
Key results — prognostic performance
Both reports reconfirmed BCI’s prognostic value in premenopausal HR+ disease.
– BCI (continuous index) predicted distant recurrence in node‑negative (N0) and node‑positive (N1) subgroups. Reported hazard ratios per unit increase in the BCI index were statistically significant: N0 HR 1.27 (95% CI, 1.11–1.44; P < .001) and N1 HR 1.58 (95% CI, 1.21–2.05; P < .001).
– Twelve‑year DRFI estimates in N0 cancers stratified by BCI risk category were clinically meaningful: 96.3% (low‑risk), 90.3% (intermediate‑risk), and 84.9% (high‑risk) in the TEXT analysis; similar gradation was reported in SOFT (for example, 95.9%, 90.8%, and 86.3% in a separate N0 subgroup analysis).
Interpretation and clinical implications
The combined evidence clarifies two related but distinct points:
- BCI is a validated prognostic tool in premenopausal HR+ breast cancer. Its continuous and categorical outputs meaningfully stratify 10–12 year distant recurrence risk and therefore can inform discussions about the baseline need for treatment intensification.
- BCI(H/I) appears to predict which tumors derive benefit from the addition of OFS to tamoxifen (SOFT): tumors with H/I‑low biology showed the clearest absolute benefit from OFS-containing regimens versus tamoxifen alone. However, BCI(H/I) does not clearly identify patients for whom exemestane+OFS is superior to tamoxifen+OFS; the TEXT analysis found benefit of exemestane+OFS across H/I strata and no significant interaction.
Clinical translation: For a premenopausal patient with HR+ disease, a low BCI(H/I) result supports consideration of OFS‑containing therapy (either tamoxifen+OFS or exemestane+OFS), especially when clinicopathologic risk is substantial. However, choosing between tamoxifen+OFS and exemestane+OFS should still be individualized based on adverse-effect profiles, bone health, fertility considerations, patient preference, and other risk factors rather than BCI(H/I) alone.
Biological plausibility and mechanistic notes
HOXB13 and IL17BR are molecular markers linked to estrogen signaling and endocrine responsiveness. A high HOXB13/IL17BR ratio has been associated with endocrine resistance phenotypes in prior studies, which supports the concept that H/I status could predict differential sensitivity to endocrine intensification. The current data suggest that H/I may mark tumors that benefit from the presence or absence of ovarian estrogen production being suppressed (i.e., addition of OFS to tamoxifen), but not necessarily which type of endocrine agent added to OFS (aromatase inhibitor vs tamoxifen) will be optimal.
Limitations and considerations
– Prospective‑retrospective design: although specimens were tested blinded to outcome, these analyses are not equivalent to a prospective biomarker‑stratified randomized trial and are subject to selection bias from available tissue.
– Different comparator contrasts: SOFT compared OFS‑containing regimens to tamoxifen alone while TEXT compared two OFS‑containing regimens; hence predictive claims are context-dependent and not interchangeable.
– Statistical interaction interpretation: lack of significant interaction in TEXT does not prove absence of differential biology; power to detect interaction and time-varying effects (some exploratory analyses suggested potential differences in years 0–5 vs >5) complicate interpretation.
– Generalizability: cohorts came from large international trials but represent patients meeting trial inclusion criteria; applicability to very low‑risk or substantially older premenopausal patients may be limited.
Practical recommendations
– Use BCI primarily as a prognostic tool to inform long-term recurrence risk discussions in premenopausal HR+ disease.
– Consider BCI(H/I)-low status as supporting evidence to discuss OFS‑based intensification (OFS + tamoxifen or OFS + aromatase inhibitor) in patients whose baseline clinicopathologic profile already suggests meaningful absolute benefit; BCI should not be the sole determinant.
– Do not use BCI(H/I) alone to mandate choice of exemestane+OFS over tamoxifen+OFS; clinical factors and patient values remain essential for that decision.
Conclusion
These two complementary analyses confirm that BCI provides reproducible prognostic information in premenopausal HR+ breast cancer. BCI(H/I) appears to predict which tumors derive benefit from adding OFS to tamoxifen (SOFT), but it does not reliably distinguish the relative benefit of exemestane+OFS versus tamoxifen+OFS (TEXT). Integration of BCI into multidisciplinary decision‑making can refine individualized treatment planning, particularly when weighing the tradeoffs of OFS, but it should be applied in the context of clinicopathologic risk, patient preferences, and careful discussion of adverse effects.
Funding and trial registration
Funding and registration details are reported in the parent TEXT and SOFT trial publications and in the BCI translational reports. The BCI analyses were performed on archived trial specimens with blinded testing as described in the cited JAMA Oncology and JAMA Network Open reports.
References
1. O’Regan RM, Zhang Y, Fleming GF, et al. Breast Cancer Index in Premenopausal Women With Early-Stage Hormone Receptor-Positive Breast Cancer. JAMA Oncol. 2024 Oct 1;10(10):1379-1389. doi: 10.1001/jamaoncol.2024.3044 IF: 20.1 Q1 . PMID: 39145953 IF: 20.1 Q1 ; PMCID: PMC11327904 IF: 20.1 Q1 .
2. O’Regan RM, Ren Y, Zhang Y, et al. Assessment of Adjuvant Endocrine Therapy With Ovarian Function Suppression by Breast Cancer Index. JAMA Netw Open. 2025 Nov 3;8(11):e2540931. doi: 10.1001/jamanetworkopen.2025.40931 IF: 9.7 Q1 . PMID: 41182766 IF: 9.7 Q1 ; PMCID: PMC12584034 IF: 9.7 Q1 .
