Chien, J.

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 Intro: The 70-gene MammaPrint (MP) assay is prognostic for distant recurrence and predictive of benefit from adjuvant chemotherapy (CT) benefit established on surgical tissue of systemically untreated patients (pts). The MP index range is from -1 to +1 with higher index indicating lower risk of early recurrence. Risk is categorized as MP High Risk, MP Low Risk, and MP UltraLow Risk, and results can guide treatment decisions. Pts with MP index >0 are classified as Low Risk and derive little benefit from CT. There are clinical scenarios in which the only available tissue for MP or other genomic testing has been exposed to neoadjuvant endocrine therapy (NET). Few studies have investigated the impact of ET exposure on MP index. Methods: Pts were identified through the I-SPY Low Risk Registry (LRR), an observational sub-study which enrolled pts with hormone receptor positive (HR+)/HER2-negative early breast cancer ineligible for the I-SPY2 trial due to MP Low Risk or UltraLow Risk status, between 2010-2020. Pts were treated at the discretion of their provider. We conducted a retrospective analysis of MP index from paired tumor tissue obtained from systemically untreated diagnostic core biopsies and surgical specimens after NET. MP categories and index before and after NET were compared. Change in MP index was assessed for an association with changes in clinicopathologic factors obtained through the LRR using the paired-t test. Results: 28 pts with paired tumor samples were included in the analysis. Median age was 48 (range 31-75) and 18 (64%) were premenopausal. At baseline, 13 (46%) were clinically node-positive and 22 (76%) had ductal histology. Tumor grade was 1 in 6 pts (21%), 2 in 20 pts (71%), and 3 in 2 pts (7%). ER expression was >95% in 25 pts (range 60-100%) and PR expression was >90% in 14 pts (range 0-100%). NET regimens included tamoxifen +/- ovarian function suppression (OFS) in 3 pts (10.7%), aromatase inhibitor (AI) +/- OFS in 15 pts (53.6%), tamoxifen followed by or in combination with AI +/- OFS in 8 pts (28.6%), fulvestrant in 1 pt (3.6%) and OFS alone in 1 pt (3.6%). 11 (61%) of premenopausal pts received OFS. 96% (27/28) of pts were classified as Low Risk both pre- and post-NET. Only one pt had MP change from Low Risk to High Risk. Three pts had change from Low Risk to UltraLow Risk or vice versa. As a continuous variable, a small average increase in MP index was observed after NET; but, there was a range of responses. 19 pts (68%) had an increase in MP index after NET, while 9 pts (32%) had a decrease. In those with a decrease in MP index, the average ER expression decreased by -13.6%, whereas in those with an increase in MP index, ER expression was unchanged (-0.18%) (p=0.049). There was no significant difference in changes in PR expression between tumors with increased vs decreased MP indices. At a median follow-up of 35 months, 4 distant recurrences were observed. Of the 9 pts with a decrease in MP index, 3 pts (33%), including the one who changed from Low Risk to High Risk, experienced a distant recurrence. In contrast, in those with an increase in MP index, 1 of 19 (5%) experienced a distant recurrence. Conclusion: In pts with early-stage HR+/HER2- MP Low Risk or UltraLow Risk breast cancer, NET had minimal impact on the tumor MP classification. These data suggest that the MP assay could be used for tissue exposed to NET if untreated tissue is not available. Further investigation in larger cohorts is needed to validate these findings. The observation that there were more distant recurrences in pts with tumors that had an increase in MP after NET is hypothesis generating, and potentially clinically relevant if validated in a larger study. The potential of MP as a dynamic risk marker to stratify recurrence risk following NET is being evaluated in the ongoing I-SPY2 Endocrine Optimization Pilot. Citation Format: S. Jacob, C. Wu, A. Glas, C. Yau, L. Brown-Swigart, G. Hirst, T. Haddad, K. Giridhar, A. Elias, R. Mukhtar, L. Huppert, K. Albain, D. Yee, L. van’t Veer, L. Esserman, J. Chien. Impact of Neoadjuvant Endocrine Therapy on MammaPrint Index in Hormone Receptor-Positive, HER2-Negative MammaPrint Low Risk Early-Stage 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 PS4-05-28.

Abstract Background Invasive lobular carcinoma (ILC) differs from invasive ductal carcinoma (IDC) in its estrogen receptor (ER) signaling pathways, response to systemic therapy, and imaging features. We evaluated differences in early change in the proliferation marker Ki67 and features on magnetic resonance imaging (MRI) after novel endocrine based neoadjuvant therapy in lobular versus non-lobular cases on the I-SPY2 EOP Trial. Methods EOP is a prospective, randomized NET trial enriched for patients with ILC. Patients with stage II-III ER positive HER2 negative breast cancer with low molecular risk (Mammaprint low or Mammaprint Hi1 plus high Sensitivity to Endocrine therapy Index) were randomized to one of several endocrine therapy-based arms. Treatment arms include novel oral SERDS with or without CDK4/6 inhibitor, aromatase inhibitors, and SERMs with or without ovarian function suppression in pre-menopausal patients. Patients undergo repeat core needle biopsy with central Ki67 assessment after 3 weeks of treatment and serial breast MRI. Here, we compare endocrine therapy responsiveness as measured by change in Ki67 at 3 weeks and functional tumor volume (FTV) on pre-surgical MRI in lobular versus non-lobular cases. Results We evaluated 253 patients of whom 148 (58.5%) had non-lobular cancer (93.9% IDC), and 105 (41.5%) had lobular cancer (17.1% mixed ILC/IDC). Overall, mean age was 53.3 years, 63.8% of tumors were grade 2, and 86.5% were Mammaprint (MP) Low with the remaining being Hi1, with higher rates of MP Low in the lobular versus non-lobular cohorts (92.4% versus 83.4%, p=0.0358). At baseline, tumors in the lobular cohort had significantly lower mean Ki67 than those in the non-lobular cohort (11.2% [SD 12.8] versus 16.4% [SD 14.4%], p=0.0038). Consistent with this, the proportion with baseline tumor Ki67 <10% was significantly higher in the lobular cohort than the ductal cohort (60.4% versus 39.3%, p=0.001). At 3-week biopsy, mean Ki67 remained lower in the lobular versus non-lobular group (3.4% versus 5.4%, respectively, p=0.0415). The proportion of patients with Ki67 <10% at 3 weeks did not differ significantly between lobular and non-lobular cases (88.6% versus 79.7%, respectively, p=0.08). Among the 40 lobular cases and 88 non-lobular cases with baseline Ki67 ≥10%, week 3 Ki67 decreased to <10% in 90% of lobular cases and 72.7% of non-lobular cases (p=0.07). On MRI, mean FTV at baseline was similar among lobular and non-lobular cases (21 cc3 versus 16.3 cc3). On pre-surgical MRI, patients in the lobular cohort had significantly higher mean residual FTV than those in the non-lobular cohort (5.7 cc3 versus 3.8 cc3, p=0.034). Interestingly, when splitting the lobular cohort into mixed lobular and pure lobular, mean residual MRI FTV was 7.5 cc3 in mixed cases and 3.8 cc3 in pure lobular cases, reflecting that FTV decreased the least in mixed lobular cases (decrease of 51.1% in mixed cases, 69.7% in pure lobular cases, and 73.9% in non-lobular cases, p=0.0255). Conclusions These results highlight differences in lobular versus non-lobular breast cancer. Lobular cases had lower baseline Ki67, and similar rates of decrease in Ki67 after 3 weeks of NET than non-lobular cases. Despite this, mean FTV after completion of 6 months of NET was higher in lobular tumors. These findings may reflect differences in early versus late indicators of response to NET, or differential response patterns by histology. Alternatively, standard response measures such as Ki67 and FTV may need lobular-specific modifications. Ongoing work includes central assessment of Ki67 from surgical specimens, analysis of changes in gene expression signatures, and evaluation of surgical outcomes such as breast conservation rates by histologic subtype. Citation Format: R. Mukhtar, P. Norwood, A. Borowsky, S. Alkhafaji, K. Giridhar, C. Vaklavas, A. Elias, M. Wei, M. Goetz, N. Onishi, O. Olopade, L. Van 't Veer, L. Huppert, W. F. Symmans, L. Brown Swigart, C. Wu, C. Yau, D. Yee, M. Magbanua, E. Price, N. Hylton, L. Esserman, J. Chien. Differential early response to neoadjuvant endocrine therapy in lobular versus non-lobular breast cancer on the Endocrine Optimization Pilot (EOP) of the I-SPY2 Trial [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 PS4-02-01.

Abstract BACKGROUND: EOP is an I-SPY2 sub-study designed to test novel endocrine-based strategies in patients (pts) predicted to have modest benefit from chemotherapy. Vepdegestrant is a selective oral PROTAC estrogen receptor (ER) degrader that has demonstrated efficacy in mutant ER+ HER2-negative MBC. METHODS: EOP eligibility included pts with Stage 2/3 HR+ HER2-negative, MammaPrint (MP) Low Risk BC. Patients with MP High1 signatures were eligible if clinically node-negative or SET 2,3 High. Pts were randomized to one of 3 oral treatment (tx) arms: vepdegestrant 200 mg/d (V), vepdegestrant 200 mg/d +letrozole (VL), vepdegestrant 200 mg/d + abemaciclib 150 mg bid (VA). Pts received tx for six 28-day cycles followed by surgery. Premenopausal (PreMN) pts received ovarian function suppression (OFS) starting C1D1 in the VL arm, and C2D1 in the V and VA arms. The primary endpoint was feasibility, defined as >75% of pts completing >75% of study therapy. Breast MRI functional tumor volume (FTV) and ctDNA (tumor-informed assay) were assessed at baseline (T0), 3 weeks (T1), 12 weeks (T2), and 6 months (T3). Ki67 and ER/PR by IHC were centrally assessed from tumor biopsies at T0, T1, and the surgical specimen. Results: Between 4/2023 and 1/2025, 121 pts were enrolled: 40 in V, 41 in VL, and 40 in VA. Median age was 54 years, 50% preMN. 60% of pts had ductal, 35% lobular, 5% mixed histology. 55% were cN+, and 59% were not breast conservation surgery (BCS) candidates at baseline. Mean baseline Ki67 was 12.5%, 85.1% had MP Low Risk signature, 79.3% were SET 2,3 High. All 3 tx arms met the primary endpoint with 88%, 88%, and 83% completing > 75% study therapy in V, VL, and VA (thus far), respectively. Most common all grade (AG) TRAEs in V and VL arms include fatigue (53% V, 71% VL), hot flashes (48% V, 71% VL), arthralgias (33% V, 49% VL), all G1 or G2 except for 1 G3 fatigue in VL arm. G2 and G3 neutropenia was seen in 1 pt each in V and VL arms. The most common AG TRAEs in VA include diarrhea (80%), fatigue (65%), nausea (58%), hot flashes (50%), neutropenia (43%). High grade TRAEs in VA include neutropenia (23% G3, 5% G4), ovarian cyst requiring surgery (5% G3), diarrhea (15% G3), nausea (3% G3), transaminitis (3% G3), thromboembolic event (8% G3), acute kidney injury (3% G3). Table 1 summarizes key response endpoints by tx arm. CONCLUSION: Six months of neoadjuvant vepdegestrant, alone or in combination with letrozole or abemaciclib, is feasible and demonstrates robust ER/PR degradation. Encouraging anti-tumor activity through reduction of Ki67 and MRI FTV, ctDNA clearance, and achievement of BCS was seen in pre- and postMN women. The neoadjuvant setting provides a rich platform to identify the dynamic range of response and non-response using a multi-modal approach and can be leveraged to inform future trial design and adjuvant therapy. Citation Format: J. Chien, R. M. Mukhtar, C. Yau, A. D. Elias, A. M. Wallace, N. Chan, C. Omene, N. Chen, J. Tseng, M. S. Trivedi, E. Stringer-Reasor, D. Yee, A. S. Clark, A. Thomas, H. Han, M. Arora, C. Nangia, K. Albain, C. Falkson, C. Isaacs, A. Zimmer, M. Rozenblit, L. van't Veer, L. Brown Swigart, G. Hirst, W. Symmans, A. D. Borowsky, N. Onishi, N. Hylton, S. Alkhafaji, K. V. Giridhar, C. Vaklavas, M. Wei, M. P. Goetz, O. Olopade, L. Huppert, C. Wu, L. J. Esserman. I- SPY2 Endocrine Optimization Pilot (EOP): Neoadjuvant vepdegestrant monotherapy or in combination with letrozole or abemaciclib in molecularly selected patients with stage 2/3 HR+ HER2-negative breast cancer (BC) [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 PD10-02.