Goetz, M. P.

Abstract Background: The Breast Cancer Index (BCI) is clinically validated to stratify patients with hormone receptor-positive (HR+), early-stage BC based on the risk of overall (0-10 years [y]) and late (5-10 y) distant recurrence (DR) with N0/N1 lymph node involvement. Validation of BCI in patients with HR+ HER2+ BC has been limited, especially in patients treated with adjuvant trastuzumab-based chemotherapy. The HOXB13 and IL17BR genes constitute the predictive component of BCI and are known to exhibit an ER-dependent correlation pattern with HER2. We evaluated the prognostic performance of BCI in patients with HR+ HER2+ disease enrolled in the NCCTG N9831 (Alliance) trial treated with the combination of chemotherapy and trastuzumab. Methods: All available tumor specimens from patients with HR+ HER2+ N0/N1 BC in arms B (sequential trastuzumab) and C (concurrent trastuzumab) of the trial were included. BCI testing was performed blinded to clinical outcomes. The primary endpoint was distant recurrence-free interval (DRFI). BCI (N0) and BCIN+ (N1) risk groups were calculated based on prespecified cut points. Kaplan-Meier analysis and log-rank testing were used to assess the prognostic significance of BCI/BCIN+ risk groups based on DR. Cox proportional hazard models with and without clinical covariates were used to estimate hazard ratios (HRs), and the associated 95% confidence intervals (CIs). Results: A total of 454 HR+ patients (234 arm B, 220 arm C), including 69 N0 and 385 N1 patients, were analyzed (median age was 47 y, 85% N1, 55% T2, 63% G3). BCIN+ scores were available for 378 of the 385 N1 patients due to missing tumor grade for 7 patients. The median follow-up was 12.7 years. In the overall cohort, BCI/BCIN+ stratified 51 (11%), 24 (5%) and 372 (83%) patients as low-, intermediate- and high-risk with 10-y DRFI rates of 96% (95% CI: 84-99%), 100% (100-100%) and 89% (86-92%), respectively. Since the low and intermediate risk groups had few patients and a similar risk of 10-y DRFI, they are combined into a single low-risk group hereafter. Thus, for overall 10-y DR, 75 (17%) and 372 (83%) of patients were classified by BCI/BCIN+ as low and high risk with 10-y DRFI rates of 97% (95% CI: 89-99%) and 89% (95% CI: 86-92%), respectively (HR=4.50, 95% CI: 1.09-18.61; p = 0.038). BCI/BCIN+ remained statistically significant in the multivariable analysis, adjusting for age, treatment, and nodal status (HR=7.54, 95% CI: 1.34-42.64; p = 0.022). For 69 N0 patients, BCI stratified 54 (78%) and 15 (22%) patients as low and high risk with 10-y DRFI rates of 100% (95% CI, 100-100%) and 77% (95% CI, 44-92%), respectively (p = 0.012). For 378 N1 patients, BCIN+ stratified 21 (6%) and 357 (94%) of patients as low and high risk with 10-y DRFI of 90% (95% CI, 66-97%) and 90% (95% CI, 86-93%), respectively (p = 0.07). Of the 21 patients classified as BCIN+ low-risk, two had BCIN+ scores of 6.75 and 6.73 in close proximity to the cut point (6.93) and experienced DR after 5 years, resulting in the same 10-y DRFI for both BCIN+ low- and high-risk patients. Conclusions: BCI is significantly prognostic for the risk of overall DR (0-10 y) in patients with HR+ HER2+ disease treated with adjuvant trastuzumab-based chemotherapy. Optimization of BCI cut points may further improve prognostic performance in HR+ HER2+. Additional validation in other HR+ HER2+ cohorts treated in the modern setting with anti-HER2-based therapy is warranted, given the small sample size of N0 patients and relatively low DR rate in the late recurrence cohort. In summary, these results provide further evidence of BCI’s utility to support clinical decision-making for adjuvant endocrine therapies for HR+ HER2+ BC. Support: U10CA180821, U10CA180882, U24CA196171, Genentech; Clinicaltrials.gov Id: NCT00005970; https://acknowledgments.alliancefound.org. Citation Format: S. Chumsri, E. Liu, K. Edwards, Y. Wen, Y. Zhang, A. K. Anderson, A. H. Partridge, L. Carey, K. Ballman, E. Perez, K. Treuner, M. Goetz, E. Thompson. Prognostic performance of Breast Cancer Index in patients with early-stage HR+ HER2+ breast cancer (BC) treated with adjuvant trastuzumab: NCCTG N9831 (Alliance) [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS3-08-08.

Abstract Purpose Background parenchymal enhancement (BPE), the contrast enhancement of normal fibroglandular tissue on dynamic contrast-enhanced breast MRI, is hormonally dependent and fluctuates with the menstrual cycle, lactation, and pregnancy. In patients with breast cancer, both endocrine therapy and chemotherapy can decrease BPE levels during treatment. Notably, a lack of BPE suppression was associated with inferior response after neoadjuvant chemotherapy in hormone receptor-positive (HR+) cancer. In HR+ breast cancer, BPE may be particularly relevant as estrogen fuels the tumor’s growth. However, there is limited clinical research directly comparing BPE and serum estradiol levels. This study aimed to investigate 1) the correlation between BPE and serum estradiol levels in treatment-naïve premenopausal patients with HR+ breast cancer and 2) the association between BPE suppression and serum estradiol suppression during neoadjuvant endocrine therapy (NET). Methods We retrospectively reviewed data from premenopausal patients enrolled in the Endocrine Optimization Pilot (EOP), a sub-study of the I-SPY 2 TRIAL, which tests new endocrine strategies in patients with stage 2/3, MammaPrint (MP) low-risk (index 0 to 1), HR+/HER2-negative (HER2-) breast cancer. Patients with MP High1 (index -0.57 to 0) tumors were eligible if clinically node negative. This study included 58 EOP patients who had both serial serum estradiol levels (drawn monthly) and BPE data available. These patients started ovarian function suppression (OFS) at various times based on their assigned treatment regimen: before NET start, n=28; at cycle 1, n=16; at cycle 2, n=14. The average estradiol levels over six months on NET were categorized into two groups: suppressed to the postmenopausal range (<10 pg/mL) or non-suppressed (≥10 pg/mL). MRI scans at baseline (before NET) and pre-surgery (after six months of NET) were analyzed. BPE was calculated on the contralateral breast as the mean early (∼150s post-contrast injection) percent enhancement of the central 50% of the axial slices. The Spearman’s correlation coefficient and the Wilcoxon rank-sum test were used to examine the relationship between BPE and estradiol. Results Treatment-naïve estradiol levels were available for 25 of the 58 patients, with the median [1st, 3rd quartile] of 82.7 [32.4, 250] pg/mL. A positive correlation was observed between treatment-naïve estradiol and baseline BPE, with a correlation coefficient of ρ = 0.74 (p < 10-5). There was no significant difference in the treatment-naïve estradiol levels between patients who later showed estradiol suppression to the menopausal range during NET (n=14 [56 %]) and those who did not (n=11 [44 %]) (81.3 pg/mL versus 86.5 pg/mL, respectively (p=0.39)). During NET, estradiol levels were suppressed to the postmenopausal range in 26 of the 58 patients (45%). Estradiol suppression was significantly associated with greater reduction in post-treatment BPE: -42.7% [-54.3, -21.8] BPE reduction for the suppressed estradiol group versus -15.0% [-40.6, 6.85] for the non-suppressed estradiol group (p=0.002). Conclusion This study demonstrates the estrogen dependency of BPE in premenopausal patients with HR+/HER2- breast cancer. Baseline estradiol levels positively correlated with baseline BPE, and the suppression of on-treatment estradiol was associated with greater BPE suppression following NET. Our findings further support exploration of the use of BPE as a reflection of estradiol level under NET and OFS in addition to other MRI biomarkers such as functional tumor volume. These complementary imaging biomarkers could independently reflect both non-malignant and tumor-specific biological processes to improve predicted performance. Citation Format: S. Choi, N. Onishi, P. Metanat, R. Mukhtar, K. Giridhar, M. P. Goetz, L. Huppert, A. Elias, O. Olopade, I-SPY2 Imaging Working Group, I-SPY2 Investigator Network, L. Esserman, J. Chien, N. Hylton. Correlation between MRI background parenchymal enhancement and serum estradiol in premenopausal patients on neoadjuvant endocrine therapy for breast cancer [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS3-07-22.

Abstract Background: (Z)-endoxifen (ENDX) is an oral SERM that dually targets ERα (> 5 ng/ml) and PKCβ1 (>500 ng/ml). It has been tested in the endocrine resistant setting at doses of 20-360 mg/day; however, the optimal dose in an endocrine naïve population is not defined. We explored 10 mg/day dose of neoadjuvant ENDX in the Endocrine Optimization Pilot (EOP) of I-SPY2. Methods: EOP eligibility included pts with Stage II/III HR+ HER2- breast cancer, MammaPrint (MP) low. Pts with MP High1 scores were eligible if clinically node-negative. Pts received ENDX 10 mg orally once daily for 6 cycles (each cycle = 28 days). Premenopausal pts started ovarian function suppression on cycle 2, day 1. ENDX was continued until the day prior to surgery. The primary study endpoint was feasibility, defined as >75% of pts completing >75% of ENDX. Baseline (T0), 3-wk (T1) biopsies, and the surgical specimen (T3) were assessed centrally for Ki-67. Rates of modified preoperative endocrine prognostic index (mPEPI) 0 were reported, defined as pT1-2 pN0, Ki67< 2.7%, or pathologic complete response. A genomic index for sensitivity to endocrine therapy (SET) index was done at T0. Breast MRI measurement of functional tumor volume (FTV) was performed at T0, T1, 12 weeks (T2), and pre-operatively (T3). Blood was collected for tumor informed ctDNA at T0, T1, T2, T3 and for pharmacokinetic (PK) steady state concentrations (Css) at T1. Safety data using CTCAE V5 is reported. Results: Between March 2023 and May 2024, 20 pts were enrolled in this arm. The median age was 52.5 years (range 32 -73), 13 (65%) were premenopausal, and 55% had clinically positive lymph nodes. Tumors were MPHigh1 in 3 pts (15%) and SET2,3 index high in 16 pts (80%). The primary endpoint was met with 95% of study participants completing ≥75% of therapy. The T0 median Ki-67 was 10.5% (range 2-60%). At T1 (n=19) and T3 (n=18), median Ki-67 was 5% (range 0-35%) and 5% (range 0-45%), respectively. The 3-week rate of Ki-67 ≤10% at T1 was 61.5% in premenopausal and 71.4% in postmenopausal women. The rate of Ki-67 ≤10% at surgery was 81.8% in premenopausal and 57.1% in postmenopausal women. An mPEPI score of 0 was observed in 1 (5%) of participants. The median T0 FTV was 8.9 ccs (range 0.9 to 251.1). The median T3 FTV was 1.3 ccs (range 0 to 11.2) and the median change in FTV from T0 to T3 was -72.0% (range -88.5% to -61.6%). ctDNA analysis was performed in 17 pts longitudinally across 64 blood samples.10 pts had positive ctDNA at T0, with 7 converting to ctDNA undetectable during treatment with ENDX. 1/7 pts who was ctDNA negative at T0 became positive at T1 and then reverted to undetectable ctDNA. The other 6 pts remained ctDNA negative at all timepoints. The median ENDX T1 Css was 79.3 ng/mL (range 73.6 - 906.4 ng /mL). The most common side effects reported were Grade 1 hot flush (70%), nausea (40%), fatigue (40%), and insomnia (35%). Grade 2 side effects included fatigue (15%) and night sweats (5%). No dose reductions or discontinuations due to toxicity occurred. Conclusions: ENDX at 10 mg was well tolerated and demonstrated reductions in Ki-67, MRI FTV, and ctDNA. The ISPY2 EOP is currently enrolling patients to ENDX 40 mg/day (intended to dually target ERα and PKCβ1) in combination with abemaciclib (with and without OFS). Citation Format: K. V. Giridhar, M. P. Goetz, C. Yau, A. M. Wallace, C. Falkson, J. Boughey, M. Arora, E. Stringer-Reasor, C. Nangia, C. Gallagher, A. Elias, A. Zimmer, M. S. Trivedi, C. Omene, L. van 't Veer, L. Brown Swigart, G. L. Hirst, W. Symmans, A. D. Borowsky, N. Onishi, N. Hylton, C. Vakalvas, M. Wei, J. M. Reid, S. Alhafaji, N. Chen, R. M. Mukhtar, L. Huppert, O. Opopade, L. J. Esserman, A. Chein. Low dose (Z)-endoxifen in the I-SPY2 Endocrine Optimization Pilot [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS3-07-10.

Abstract Introduction: Patients with ER+/HER2- breast cancer associated with germline pathogenic variants (PVs) in BRCA1, BRCA2 and CHEK2 exhibit distinct clinicopathological features compared to sporadic cases. However, the optimal endocrine therapy strategies for these patients remain undefined. The Breast Cancer Index (BCI) is a validated gene expression-based signature that stratifies patients based on the risk of overall (0-10 years) and late (post-5 years) distant recurrence and predicts the likelihood of benefit from extended endocrine therapy (EET) in early-stage, HR+ breast cancer. Here we utilize BCI to investigate endocrine sensitivity and the predicted EET benefit in a cohort of ER+/HER2- breast cancer patients with BRCA1, BRCA2 and CHEK2 PVs. Methods: BRCA1, BRCA2 and CHEK2 PV carriers with ER+/HER2- breast cancer diagnosed at Mayo Clinic between 1996 and 2024 at Mayo Clinic were identified from a registry tracking germline test result. For comparison, we utilized the BCI Registry, a prospective, multi-institutional tumor registry of patients with early-stage ER+/HER2- breast cancer undergoing BCI testing, regardless of germline PV status. The analysis was restricted to women with invasive, early-stage locoregional breast cancer and available pre-treatment tumor specimens. BCI testing was performed by RT-PCR blinded to clinical outcome. BCI prognostic and BCI predictive categories were compared between the Mayo Clinic germline PV cohort and the BCI Registry using descriptive statistics and Fisher’s exact test. Results: The final analysis included 123 PVcarriers (BRCA1: 36; BRCA2: 40; CHEK2: 47) from the MayoClinic cohort and 2,563 women from the BCI Registry. The proportion of patientsdiagnosed before age 50 was higher among PV carriers—52.8% in BRCA1,50.0% in BRCA2, and 21.3% in CHEK2—compared to 7.0% in the BCIRegistry. PV carriers were also more likely to be premenopausal andnode-positive at diagnosis. Based on BCI score, a significant higher proportionof BRCA1 (75.0%, p=0.002) andBRCA2 (70.0%, p=0.01) PV carriers wereclassified as high risk, compared to 48.5% of patients in the BCI Registry, butno significant difference was seen for CHEK2 PV carriers (46.8%,p=0.88). A significantly higher proportion of BRCA1 PV carriers werepredicted to benefit from EET compared to the BCI Registry cohort (77.8% vs.33.9%, p<0.001), whereas no significant differences in BCI Predictivecategories were observed for BRCA2 or CHEK2 PV carriers. Overall,compared to breast cancer cases in the BCI registry, a significant differencein the distribution of the combined BCI prognostic and predictive categorieswas noted for BRCA1 (p<0.001)and BRCA2 (p=0.02) PV carriers,but not for CHEK2 PV carriers (p=0.66). In particular, BRCA1 andBRCA2 PV carriers were enriched for high-risk tumors with a high likelihoodof EET benefit (66.7% and 37.5%, respectively vs 25.1%, p<0.001 and p=0.02),whereas only a small non-significant increase was observed for CHEK2 PVcarriers (29.8% vs 25.1%, p=0.66) compared to breast cancer cases in the BCIRegistry. Conclusions: Genomicclassification by BCI reveals distinct patterns of endocrine sensitivity andpredicted EET benefit among germline PV carriers, particularly in BRCA1and BRCA2 PV carriers. These findings warrant further investigation andmay inform personalized endocrine therapy strategies for women with germlinePV-associated ER+/HER2- breast cancer. Citation Format: S. Yadav, B. O'Neal, S. Yasir, N. Siuliukina, A. Karki, Y. Zhang, A. K. Anderson, K. Treuner, M. P. Goetz, F. J. Couch. Endocrine Sensitivity and Predicted Benefit of Extended Endocrine Therapy based on Breast Cancer Index (BCI) in BRCA1, BRCA2 and CHEK2 Pathogenic Variant Carriers with ER+/HER2- Breast Cancer [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS2-08-25.