Partridge, Ann H.

PURPOSE EA1181 (ClinicalTrials.gov identifier: NCT04266249 ) is a single-arm trial evaluating neoadjuvant taxane, trastuzumab, and pertuzumab (THP) in patients with clinical stage II/IIIa human epidermal growth factor receptor 2 (HER2)–positive breast cancer. This report focuses on the secondary end points of pathologic complete response (pCR) rates and associated factors. The primary end point—3-year recurrence-free survival among patients achieving a pCR (ypT0/Tis, ypN0)—will be reported when data mature. METHODS Patients received four cycles of trastuzumab and pertuzumab (HP) with either once per week paclitaxel (12 weeks) or docetaxel (every 3 weeks for four cycles), followed by surgery. Clinicopathologic characteristics were assessed in all patients. The HER2DX pCR score was determined using diagnostic biopsy samples in a representative subset. Logistic regression models identified factors associated with pCR. RESULTS A total of 2,175 patients were enrolled (781 HER2+/estrogen receptor‑negative [ER–]; 1,394 HER2+/ER+). Of 2,141 patients who initiated THP, the overall pCR rate was 43.8%: 63.7% in HER2+/ER– and 32.4% in HER2+/ER+ tumors. Higher pCR rates were observed in tumors that were ER-negative or low ER expressing, progesterone receptor-negative or low expressing, HER2 immunohistochemistry (IHC) 3+, and in patients treated with once per week paclitaxel. T3 disease was associated with a lower pCR rate in HER2+/ER– tumors; otherwise, tumor (T) and nodal (N) stage did not significantly affect pCR. Among 569 patients assessed for HER2DX pCR scores, a high score was independently associated with higher pCR rates, after adjustment for clinicopathologic variables. CONCLUSION Neoadjuvant THP achieved pCR in nearly two-thirds of patients with HER2+/ER– and one third with HER2+/ER+ breast cancer. Low hormone receptor expression, HER2 IHC 3+ status, once per week paclitaxel use, and a high HER2DX pCR score were independent predictors of pCR. These findings should help optimize risk stratification and treatment personalization for patients with HER2-positive breast cancer.

632 Background: Prospective data on the risk of breast cancer (BC) recurrence among young BC survivors who have a subsequent pregnancy are limited. We sought to evaluate the long-term impact of pregnancy and live birth on BC outcomes in the Young Women’s Breast Cancer Study (NCT01468246), a prospective multicenter study of women aged ≤40 years at BC diagnosis. Methods: Women with stage 0-III BC without prior hysterectomy were included. The primary endpoint was breast cancer-free interval (BCFI) between patients with and without a (a) pregnancy and (b) live birth after BC. Secondary endpoints were distant recurrence-free interval (DRFI) and overall survival (OS). A time-varying Cox proportional hazards model was performed by estrogen receptor (ER) status, controlling for age at diagnosis, tumor stage, HER2 status, tumor grade, parity at diagnosis, and germline pathogenic variant status. Results: Among 1,016 BC survivors at a median follow-up of 12 (range, 0.5-18.5) years, 198 reported ≥1 pregnancy and 165 reported ≥1 live birth post-diagnosis. Among survivors who reported a post-diagnosis pregnancy, median age at diagnosis was 32 (range, 17-40) years; most had stage I (35%) or II (40%) BC, with 72% hormone receptor (HR)-positive and 25% HER2+; 42% were nulligravid and 60% were nulliparous at diagnosis. Among BC survivors who did not become pregnant post-diagnosis, median age at diagnosis was 37 (range, 21-40) years; most had stage I (35%) or II (43%) BC, with 75% HR-positive and 28% HER2+; 25% were nulligravid and 29% were nulliparous at diagnosis. Among BC survivors with ER-positive tumors (n = 737), pregnancy after BC was not associated with a difference in BCFI (adjusted hazard ratio [HR] 0.60, 95% CI 0.31-1.16, P = 0.130), DRFI (HR 0.73, 95% CI 0.35-1.55, P = 0.416), or OS (HR 0.58, 95% CI 0.24-1.40, P = 0.227). Similarly, live birth after BC did not impact BCFI (HR 0.83, 95% CI 0.45-1.55, P = 0.560), DRFI (HR 1.04, 95% CI 0.52-2.06, P = 0.923), or OS (HR 0.77, 95% CI 0.34-1.76, P = 0.541). Outcomes among BC survivors with ER-negative tumors (n = 278) were also not affected by post-diagnosis pregnancy (BCFI [HR 1.48, 95% CI 0.70-3.14, P = 0.304], DRFI [HR 1.59, 95% CI 0.68-3.75, P = 0.287], OS [HR 0.99, 95% CI 0.39-2.49, P = 0.975]) or live birth (BCFI [HR 1.02, 95% CI 0.41-2.53, P = 0.974], DRFI [HR 0.80, 95% CI 0.24-2.69, P = 0.722], OS [HR 0.39, 95% CI 0.09-1.69, P = 0.208]). Conclusions: In this multicenter, prospective study with 12 years of median follow-up, pregnancy and live birth after BC did not impact BC events or overall survival, irrespective of ER status. These long-term data from a modern cohort provide reassurance for young BC patients interested in future fertility. Clinical trial information: NCT01468246 .

566 Background: Endocrine therapy (ET) resistance (ETR) remains a primary challenge in ER+ breast cancer. Analyzing pretreatment tumor transcriptomes across trials with early response endpoints can reveal shared and specific ETR signatures. This study utilizes baseline RNA data from the Phase III ALTERNATE trial (Alliance A011106, NCT01953588; Anastrozole [A], Fulvestrant [F], or AF) and the ACOSOG Z1031B trial (NCT00824941) to identify predictors of early Ki67 response in postmenopausal ER+/HER2– patients. Methods: ETR was defined as week-4 on-treatment Ki67 >10%. Baseline gene expression from ALTERNATE was analyzed to identify differentially expressed (DE) genes (Wilcoxon test, P<0.05) and Hallmark pathways associated with ETR, both across and within individual treatment arms. Feature selection was performed using mixOmics. A Pan-Endocrine Therapy Signature (PETS) was developed by uniting DE genes identified across all three ALTERNATE arms and Z1031B. All statistical analyses were conducted in R (P<0.05). Results: Overall ETR rate in the ALTERNATE RNA-seq cohort (n=733) was 26%. ETR was associated with high Risk of Recurrence (ROR), Oncotype RS, and Mammaprint scores (calculated from RNA-seq data in research setting). In luminal tumors (n=649), ETR was linked to chr 3q13.33, 8q24.13, and 20q13.12 cytoband upregulation and 17q21, 18q23, 3p21.1, and 10q24.32 cytoband downregulation. ETR tumors showed T-cell, E2F target, and interferon-γ enrichment; sensitive tumors favored early estrogen response and muscle differentiation. At individual gene level, high MYBL2 , PIF1 , TROAP and with low HJURP predicted ETR across all samples (AUC>0.70). A deep learning model using all protein-coding genes achieved AUC 0.82 (training) and 0.79 (test) in predicting ETR. Cross-trial integration identified ETR-associated PETS, enriched for genomic instability. PETS performed comparably to established signatures and strongly correlated with MYBL2 signature (r=0.93). Top ETR predictors were MYBL2 , AURKB , and EME1 for Arm A and IL4I1 , TNFAIP6 , and ANLN for Arm AF. AF-resistant tumors were enriched for systemic lupus and RIG-I–like receptor signaling; sensitive tumors favored PI3K–AKT, EGFR TKI resistance, AMPK, and insulin signaling. Conclusions: Baseline transcriptomics identify shared and therapy-specific ETR markers. The 15-gene PETS defines a convergent resistance signature, performing similar to established signatures in predicting ETR and correlating with MYBL2. Enrichment of cell-cycle and immune pathways in resistant tumors may suggest patient stratification approach for alternative or combinatorial strategies to overcome early ETR in ER+ breast cancer. Acknowledgement: https://acknowledgments.alliancefound.org. Support: U10CA180821, U10CA180882, U24CA1. Clinical trial information: NCT01953588 .

603 Background: Accurate prediction of pathologic complete response (pCR) after preoperative therapy for HER2-positive (HER2+) breast cancer can help triage patients to immediate surgery vs additional preoperative therapy. Pre-surgery (i.e., after neoadjuvant therapy) imaging studies may help estimate the likelihood of pCR. In EA1181, patients (pts) with stage II-IIIA HER2+ breast cancer received four cycles of preoperative taxane, trastuzumab, and pertuzumab (THP×4). Pre-surgery imaging was required, though the specific imaging modality was not mandated. Here, we report the accuracy of pre-surgery breast MRI to predict pCR (ypT0/Tis, ypN0). Methods: Among 2,141 pts treated with THPx4, 1,378 had pre-surgery breast MRI and were representative of the overall cohort, although T3 tumors were more common (16% vs 9%). MRI reports were available for 1,351 pts; all reports were centrally reviewed and classified as radiologic complete response (rCR; no residual tumor enhancement and normalization of lymph nodes, if applicable) or radiologic residual disease (rRD). Reports with indeterminate radiologic response were independently reviewed by two study radiologists blinded to pathology outcomes. Among pts with rCR who had pathologic residual disease (pRD), we also assessed the extent of residual disease by residual cancer burden (RCB) score. Among pts with rRD who had a pCR, we determined the proportion who only had residual ductal carcinoma in situ (DCIS). Results: See Table. Conclusions: After neoadjuvant therapy, preoperative MRI accurately predicted pCR in 86% of patients with HER2+/ER− disease and may help identify patients who can proceed directly to surgery. MRI is insufficient to predict pCR for pts with HER2+/ER+ disease, as only 55% with complete response on MRI had a pCR at surgery. A pre-surgery MRI that indicated residual disease was accurate in 80% of pts with HER2+/ER+ disease, but in only 45% of pts with HER2+/ER- cancer. Accurately predicting residual disease after THPx4 allows for consideration of additional therapy that may increase the chance of pCR. Combining imaging like MRI with other biomarkers, such as tissue-based markers or circulating tumor DNA, may improve prediction of pCR and facilitate personalization of treatment decisions in HER2+ breast cancer. All pts with pre-surgery MRI (n=1351)pCR rate overall in this cohort = 47% MRI result Pathology pCR pRD rCR 70.6% (341/483) 29.4%(142/483) 78% had RCB1 rRD 34%(295/868) 21% of 295 had DCIS only 66.01% (573/868) ER- (n=589)*Overall pCR rate in ER- subset = 68% MRI result Pathology pCR pRD rCR 86.1% (205/238) 13.9% (33/238) 85% had RCB1 rRD 55.3% (194/351) 19% of 194 had only DCIS 44.7% (157/351) ER+ (n= 762)*Overall pCR rate in ER+ subset = 31% MRI result Pathology pCR pRD rCR 55.5% (136/245) 44.5% (109/245) 76% had RCB1 rRD 19.5% (101/517) 26% of 101 had only DCIS 80.5% (416/517)

12010 Background: BWEL (Alliance A011401; NCT02750826) is a Phase III trial that randomizes patients (pts) with stage II-III breast cancer and body mass index (BMI) ≥27 kg/m 2 1:1 to a 24-month (mo) lifestyle-based WLI + health education (HE) or HE alone. Here we report prespecified secondary outcomes of the impact of the WLI on patient-reported QOL and symptoms. Methods: The first 540 BWEL pts (randomized between 9/2016 and 7/2017) were included in this substudy that collected PROMIS 29 Profile 2.0 and Global Health scores at enrollment, 6 and 24 mos. Adjusting for baseline scores, mean physical function (predefined substudy primary outcome), global physical and mental health, fatigue and other scores were compared at 6 and 24 mos using analysis of covariance (ANCOVA). P-values <0.05 were considered significant. Positive differences in positive attributes (e.g., physical function) and negative differences in negative attributes (e.g., anxiety) represented better outcomes in the WLI arm. Results: At baseline, median BMI was 32.9 kg/m 2 (26.5 – 69.1), median age was 53 (25 - 78) years; 83.9% of pts were non-Hispanic White, 10.7% were Black and 5.9% were Hispanic. At 6 mos, the WLI (vs HE) arm had significantly better physical function (ANCOVA-based mean difference between arms 1.9 [95% CI 0.8, 3.0]; p<0.001), global physical health (2.0 [95% CI 0.9, 3.0]; p<0.001), global mental health (1.30 [95% CI 0.2, 2.4], p=0.03), social roles and activities (2.3 [95% CI 1.1, 3.6]; p<0.001), and fatigue (-1.7 [95% CI -3.1, -0.4], p=0.01) (Table). Improvements were generally maintained at 24 mos. Similar findings were seen in analyses using longitudinal mixed modeling. Conclusions: The BWEL WLI demonstrated QOL benefits for patients with breast cancer, resulting in significantly better physical function, global physical and mental health, and symptoms. Future analyses will evaluate which populations experienced the most benefit, as well as the relationships among QOL, symptoms, and weight loss. Support: U10CA180821, U10CA180882, UG1CA189823; U10CA180820; U10CA180868; U10CA180863, CCS 707213; U10CA180888; UG1CA189858; https://acknowledgments.alliancefound.org. Clinical trial information: NCT02750826 . Analysis of covariance-adjusted least squares means values at 6-mos adjusted for baseline scores. QOL/Symptom Attributes HE WLI Between arm difference (95% CI)* P value Physical Function 47.1 49.0 1.9 (0.8, 3.0) <0.001 Global Physical Health 46.2 48.1 2.0 (0.9, 3.0) <0.001 Global Mental Health 48.6 49.9 1.3 (0.2, 2.4) 0.03 Social Roles and Activities 52.7 55.0 2.3 (1.1, 3.6) <0.001 Anxiety 50.2 50.0 -0.2 (-1.6, 1.2) 0.77 Depression 47.5 47.5 -0.0 (11.2, 1.2) 0.96 Fatigue 50.6 48.9 -1.7 (-3.1, -0.4) 0.01 Sleep Disturbance 51.0 51.1 0.1 (-0.6, 0.8) 0.80 Pain Interference 51.3 50.3 -1.0 (-2.4, 0.4) 0.15 *Positive differences in positive attributes and negative differences in negative attributes favor WLI arm.

Abstract Background Whether outcomes of germline BRCA1/2 (gBRCA1/2)-associated breast cancer differ compared with sporadic tumors is controversial. We explored the impact of gBRCA1/2 pathogenic variant (PV) status beyond established prognostic features. Methods We conducted 2 retrospective, matched cohort studies comparing gBRCA1/2 PV carriers and noncarriers with HER2-negative, stage I-III breast cancer (Clinical Outcomes Quality Database [COQD] cohort: 185 carriers, 555 noncarriers; Young Women’s Breast Cancer Study [YWS] cohort: 113 carriers, 226 noncarriers). Matching factors were age, stage, hormone receptor status, and year of diagnosis. Clinicopathological features, treatments, and survival outcomes were compared between carriers and noncarriers. Results Most patients in COQD had stage I-II disease (87.2%), and more carriers than noncarriers had genetic testing before diagnosis (33% vs 5.6%, P &lt; .001). In YWS, 22.7% of patients had stage III tumors, and few were tested before diagnosis (14.8% of carriers vs 1.7% of noncarriers; P &lt; .001). Carriers in COQD received chemotherapy more often than noncarriers (81.1 vs 67.0%, P &lt; .001), including platinum (P = .010); the proportion was similar for carriers and noncarriers in YWS. After adjusting for chemotherapy, relapse-free survival was longer in carriers than noncarriers in COQD (adjusted hazard ratio = 0.48 [95% CI = 0.26 to 0.87], P = .016), and a favorable trend was observed for other survival outcomes in both cohorts. Triple-negative tumors appeared to drive the differences. Conclusions We observed a trend toward improved outcomes in gBRCA1/2 PV carriers compared with noncarriers. These findings suggest that carriers should not receive more aggressive treatment solely based on their germline mutation status. Prospective clinical trials in this population are warranted.

Abstract Background Breast cancer (BC) diagnosed during pregnancy or postpartum often presents with aggressive features, potentially influenced by hormonal, immunological, and tissue remodeling changes. Studies have suggested that postpartum BC may be associated with worse outcomes, though most evidence is retrospective and constrained by methodological limitations. This study evaluated associations between pregnancy history, recency of childbirth, and long-term outcomes in a prospective cohort of young patients with early-stage BC. Patients and Methods Patients aged ≤40 years with stage I–III BC enrolled in the Young Women’s Breast Cancer Study were categorized at diagnosis as nulligravid, nulliparous, pregnant, or parous (≤5 vs 5 to 10 years postpartum). Analyses were stratified by BC subtype (estrogen receptor-positive [ER+]/HER2−, HER2+, and triple-negative [TNBC]), with distant recurrence-free survival (DRFS) as the primary endpoint. Results Among 859 patients, 257 (29.9%) were nulligravid, 50 (5.8%) nulliparous, 37 (4.3%) pregnant, and 515 (60.0%) parous. Pregnant patients had proportionally more TNBC, nodal involvement, T3/T4, and grade 3 tumors. After 11.1 years median follow-up, pregnancy or postpartum status was not independently associated with DRFS in multivariable models adjusted for age, tumor characteristics, and treatment, with consistent findings across ER+/HER2−, HER2+, and TNBC subtypes. Sensitivity analyses, including further categorization of postpartum diagnoses (&lt;2 vs 2 to 5 years), yielded consistent results. Conclusions Pregnancy history and recency of childbirth were not independently associated with long-term DRFS. Despite more aggressive features at diagnosis, patients diagnosed during or after pregnancy had comparable outcomes after adjustment, suggesting no adverse prognostic impact. Clinical trial registration NCT01468246 (https://clinicaltrials.gov/study/NCT01468246? term=NCT01468246&rank=1).

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 Background: Women younger than 40 generally fall outside the routine screening population for breast cancer (BC). We aimed to understand factors influencing diagnosis and treatment delays in these patients, and the impact of delays on disease-free survival (DFS). Methods: We included women aged ≤ 40 years at diagnosis of stage 0-IV BC enrolled in the Young Women’s BC Study from 2006-2016. Sociodemographics, initial BC symptoms, and disease status were collected via annual surveys. Medical record review was used to capture tumor characteristics and recurrence status. We used logistic regression to estimate associations between patient and tumor factors and three delay types: (1) self-delay (≥ 90 days from first symptom to presentation to a provider), (2) diagnosis delay (≥ 90 days from healthcare visit to diagnosis), and (3) treatment delay (≥ 60 days from diagnosis to first treatment). Odds ratios (OR) and 95 % confidence intervals (CI) were estimated in multivariable models after choosing factors via backwards selection (p≤0.05 retained). Hazard ratios (HR) and 95% CIs for the association between delays and DFS, overall and by stage, were estimated via Cox proportional hazard models, adjusted for tumor and treatment factors. Time to event was measured from diagnosis or treatment to recurrence, death, or last follow-up, whichever occurred first. Results: Of 1,297 patients, 1,071 who completed the long-form baseline survey were included. Median time from first symptom to presentation was 14 days (interquartile range (IQR)=2-45), presentation to diagnosis was 14 days (IQR=7-30), and diagnosis to treatment was 41 days (IQR=25-57). Overall, 14% (n=153) had a self-delay and 11% (n=120) had a diagnosis delay. Of 839 patients with self-detected tumors, 18% had a self-delay and 13% had a diagnosis delay. Among those with Stage 1-3 BC (N=928), 22% (n=205) had a treatment delay. In univariable models, income &lt;50K (p=0.01), lower financial comfort (p=0.01), and not living with a partner (p=0.03) were associated with higher odds of self-delay, while pregnancy within 1 year pre-diagnosis (p=0.05) and first-degree family history of any cancer (p=0.04) or BC (p=0.03) were associated with lower odds. Self-delays were more likely for women diagnosed with stage 4 BC (p=0.004) or with HER2+ tumors (p=0.03) and less likely for those with triple negative (TN) BC (p&lt;0.001). In the multivariable model, family history of BC (OR=0.40, 95% CI=0.17-0.80), income &lt;50K (OR=1.97, 95% CI=1.22-3.13) and TN subtype (OR v. luminal A=0.30, 95% CI=0.13-0.60) remained associated. Odds of diagnosis delay were higher among women who were younger (p=0.01) or with Stage 4 BC (p=0.004), and lower for those with luminal B (p=0.04), TN (p=0.01), or high grade tumors (p=0.03). In the multivariable model, younger age (OR per 1-year=0.94, 95% CI=0.89-0.99), and subtype (luminal B v. A OR=0.60, 95% CI=0.38-0.95; TN v. luminal A OR=0.35, 95% CI=0.16-0.70) remained associated. Multivariable models for self-and diagnosis delays remained similar when restricted to self-detected patients.Treatment delays were less likely among unemployed individuals (p=0.001), and women with a positive germline BC risk variant (p=0.002), luminal B (p=0.005) or TN (p&lt;0.001) subtypes, and high-grade tumors (p=0.03). Only tumor factors remained significant in the multivariable model, including subtype (luminal B v. A OR=0.59, 95% CI=0.41-0.86, TN v. luminal A OR=0.25, 95% CI=0.13-0.43), and stage (stage 3 v. 1 OR=0.37, 95% CI=0.20-0.65). Overall and by stage at diagnosis, delays were not statistically significantly associated with DFS before or after adjusting for tumor and treatment factors. Conclusions: Delays in breast cancer care are influenced by multiple psychosocial and clinical factors, and disparities exist by socioeconomic status. It is critical to decrease self- and diagnosis delays to prevent stage 4 breast cancer. Citation Format: B. X. Zhang, T. Sella, Y. Zheng, G. J. Kirkner, K. J. Ruddy, S. M. Rosenberg, V. F. Borges, L. Schapira, S. E. Come, J. Peppercorn, A. H. Partridge, K. D. Brantley. Delays in breast cancer diagnosis and treatment in young women [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 PS3-02-16.

Abstract Background Central nervous system (CNS) metastases are a major clinical concern in patients with HER2-positive metastatic breast cancer (MBC). The PATINA phase III study showed improved PFS with palbociclib added to maintenance anti-HER2/endocrine therapy (44.3 vs. 29.1 months; hazard ratio 0.75; 95% CI 0.59-0.96; 1-sided P=0.0109). Preclinical and early clinical data suggest palbociclib may have CNS activity. We conducted a pre-specified secondary analysis to evaluate the incidence and timing of CNS progression. Methods CNS progression was defined as the emergence of new intracranial lesions per investigator assessment. Baseline CNS imaging was not mandated but recommended if symptomatic. Competing risks analyses evaluated time from registration to first CNS progression or death (CNS PFS), treating non-CNS progression as a competing event. All randomized patients were included in the primary analysis, regardless of known baseline CNS involvement. Patients with baseline CNS metastases were not censored if progression involved the CNS. A secondary analysis excluded patients with CNS metastases present at baseline. Cumulative incidence functions were estimated and compared using 2-sided Gray’s test. Results Data cutoff for this analysis was on October 15, 2024. 518 participants were enrolled between June 2017 and July 2021, 261 to the palbociclib arm and 257 to the control arm. CNS metastases at baseline were present in 11 patients in the palbociclib arm and 9 patients in the control arm. Among all randomized patients, CNS progression occurred in 35 of 261 (13.4%; 95% CI: 9.5-18.2) in the palbociclib arm and 50 of 257 (19.5%; 95% CI: 14.8-24.8) in the control arm. When excluding patients with CNS metastases at baseline, CNS progression was observed in 32 of 250 (12.8%; 95% CI: 8.9-17.6) in the palbociclib arm and 47 of 248 (19.0%; 95% CI: 14.3-24.4) in the control arm. The median follow-up for patients who were alive and progression-free was 53.5 months. At 36 months, the cumulative incidence of CNS PFS was 13.4% vs. 19.9% for palbociclib versus control (Gray’s test p=0.0386). Importantly, when the analysis was restricted to pts without evidence of CNS disease at baseline (Table 1), —the CNS benefit with palbociclib was maintained (13.0% vs. 19.2% at 36 months, Gray’s test p = 0.0378). Conclusion The addition of palbociclib to anti-HER2 and endocrine therapy was associated with a lower incidence of CNS metastases. Among patients without known baseline CNS involvement, the absolute reduction in CNS progression at 36 months was 6.2% in favor of palbociclib. This benefit was observed at 12 months and sustained over 3 years (Table 1). These findings suggest that palbociclib may help delay or prevent CNS involvement in HR+/HER2+ MBC, warranting confirmation in future studies. Citation Format: O. Metzger, S. Mandrekar, T. Dockter, L. Gianni, E. Ciruelos, A. De Michele, J. Gligorov, E. Lim, S. Loibl, X. Gonzàlez Farré, F. Lynce, J. Lanzillotti, L. Carey, S. Goel, A. Partridge, E. Winer. Central Nervous System Outcomes from the Phase III PATINA Trial (AFT-38) [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 RF4-01.