Positive Early Stage Breast Cancer Research Articles

Denosumab Prevents Bone Loss and Microarchitectural Deterioration in Premenopausal Women With Breast Cancer Receiving Estradiol Suppression Therapy: A Randomized Controlled Trial.

Suppression of ovarian function and aromatase inhibition (AI) increases disease-free survival in premenopausal women with estrogen receptor (ER)-positive early-stage breast cancer but accelerates bone loss. We therefore hypothesized that suppressing bone remodeling using denosumab (DMAB) would prevent bone loss in these women. In a 12-month double-blind randomized trial, 68 women with ER-positive early-stage breast cancer commencing ovarian function suppression and AI were randomly assigned to 60 mg DMAB (n = 34) or placebo (PBO; n = 34) once every 6 months (at 0 and 6 months). Volumetric bone mineral density (BMD), microarchitecture, and estimated bone strength of the distal tibia and distal radius were measured using high-resolution peripheral quantitative computed tomography, and spine and hip BMD were measured using dual-energy X-ray absorptiometry at 0, 6, and 12 months. The primary end point and treatment effect was the mean adjusted between group difference (MAD; [95% CI]) in distal tibial total volumetric BMD over 12 months, with a single P value tested over all time points. The study is registered with the Australian New Zealand Clinical Trials Registry (anzctr.org.au; identifier: ACTRN12616001051437). Intention-to-treat analysis included all 68 randomly assigned women. Over 12 months, compared with PBO, DMAB prevented the decrease in distal tibial total BMD (MAD, 20.8 mg HA/cm3 [95% CI, 17.3 to 24.2]), cortical BMD (42.9 mg HA/cm3 [95% CI, 32.1 to 53.9]), trabecular BMD (3.32 mg HA/cm3 [95% CI, 1.45 to 5.20], P = .004), estimated stiffness (11.6 kN/m [95% CI, 7.6 to 15.6]), and failure load (563 N [95% CI, 388 to 736]). Findings were similar at the distal radius. Decreases in BMD at the lumbar spine (MAD, 0.13 g/cm2 [95% CI, 0.11 to 0.15]), total hip (0.08 g/cm2 [95% CI, 0.07 to 0.09], and femoral neck (0.06 g/cm2 [95% CI, 0.05 to 0.07]) were also prevented. All P < .001 unless otherwise noted. Treatment with DMAB at commencement of estradiol suppression therapy preserves BMD, bone microarchitecture, and estimated strength, and is likely to increase fracture-free survival.

Toxicity differences in CDK 4/6 inhibitors seen in Asian and Pacific Islanders.

e13086 Background: Cyclin-dependent kinases (CDK) 4/6 inhibitors are the standard of care, first line treatment for hormone receptor positive metastatic breast cancer and adjuvant high-risk hormone receptor positive early stage breast cancer along with endocrine therapy. There have been multiple clinical trials validating the effectiveness, along with toxicities of these agents; however, the majority of these trials lack ethnic diversity. This shortcoming limits the ability to apply these findings in diverse patient populations, especially among Asian and Pacific Islanders in Hawaii. Objective: To determine if the toxicity profile of CDK 4/6 inhibitors in women with breast cancer is different among patients at a community oncology practice in Hawaii, in which the majority of patients are Asian, Pacific Islander or a combination of both when compared to three landmark trials. Methods: A retrospective analysis of thirty-two patients with hormone receptor positive, HER2 negative metastatic or high risk breast cancer who started endocrine therapy and CDK 4/6 inhibitor therapy (abemaciclib, ribociclib, or palbociclib) between 2018-2023. Graded toxicities of each individual patient based on CTCAE criteria V. 5, along with demographic data was reviewed and compared to three main registration trials for these agents (MONARCH-3, MONALEESA-2, PALOMA-2). Results: Combined results from the three large randomized trials reported an average of 75% of participants were Caucasian, as compared to 15% in the Hawaii data. While 19% percent of participants from the combined large randomized trials reported being of Asian descent, none of these trials reported a breakdown of Asians versus Pacific Islanders. In the Hawaii sample, 41% were reported as Pacific Islander and 41% reported as Asian, 15% Caucasian, with the final 3% reported as Hispanic. Collective analysis of the FDA registration trials contained 0% Pacific Islander, 19.8% Asian, 74.3% White, 1.5% Black, and 4.4% Other. The majority of all toxicities of all grades were higher in the Hawaii population as compared to the three national trials, except for neutropenia with ribociclib and diarrhea with palbociclib (Table). Conclusions: The Hawaii analysis that was primarily comprised of Asians and Pacific Islanders revealed an increased incidence of toxicities, despite starting at lower doses rates for all CDK 4/6 inhibitors. This data analysis begins to highlight the importance of representative populations in clinical trials for the most effective and safest care of diverse populations. [Table: see text]

The impact of adjuvant endocrine therapy (AET) omission in ER-low (1-10%) early-stage breast cancer.

513 Background: Adjuvant endocrine therapy (AET) improves overall survival (OS) in patients (pts) with hormone receptor (HR) positive early-stage breast cancer (BC). For pts with estrogen receptor (ER)-low BC (defined as ER 1-10%), there is controversy regarding AET benefit, given tumor heterogeneity (&gt;40% basal; (1)), and similar chemotherapy response and prognosis to ER-negative (neg) BC. Current guidelines categorize ER-low BC as a separate entity and suggest equipoise regarding AET benefit. We previously determined that AET omission in chemotherapy-treated pts with ER+ BC resulted in a nearly 2-fold increase in death (2). However, the impact of AET omission in patients with ER-low BC is unknown. Methods: Beginning in 2018, the National Cancer Database (NCDB) began to abstract ER as a continuous variable, allowing classification of ER+ tumors as 1-10% or &gt;10%. Therefore, we queried the NCDB 2018-2020 for patients with stage I-III ER+BC treated with neoadjuvant or adjuvant chemotherapy, as these pts have the highest risk of recurrence. ER was assessed as ER-neg (0%), low (1-10%) and ER &gt;10%. OS was analyzed with AET as a time-dependent covariate using Cox proportional hazards regression. Results: 357,085 pts with stage I-III ER+BC were identified, with 10,396 (3%) classified as ER-low. Among pts with ER-low disease, 69% had PR-neg BC and 67% had HER2-neg BC. The majority (77%) were treated with chemotherapy (32% neoadjuvant, 44% adjuvant, 1% unknown timing) and formed our analysis cohort. Among these 7,956 pts, AET was omitted in 3,233 (41%). AET omission was more common for pts with tumors that were PR-neg vs positive (46% vs 30%, p&lt;0.001), HER2-neg vs positive (44% vs 37%, p&lt;0.001), and Ki67≥20% (44% vs 35%, p&lt;0.001). With median follow-up of 3 years, 648 deaths were observed. OS was 94.3% (95% CI: 93.8-94.9%) at 2 years and 87.6% (95% CI: 86.5-88.7%) at 4 years. In unadjusted analysis, omission of AET was associated with worse OS (HR 1.40, 95% CI: 1.19-1.65, p&lt;0.001), with similar effects regardless of PR, HER2, or Ki67 (each interaction test p&gt;0.3). When controlling for age, comorbidity score, year of diagnosis, PR, HER2, and pathologic stage, the adjusted effect of AET omission on OS was HR 1.22 (95% CI: 1.00-1.48, p=0.05). Given assessment of OS was performed during pandemic years, with 1/3 of deaths occurring during the first year of follow-up, we performed a sensitivity analysis to analyze pts who survived to one year after definitive surgery. In this analysis, the adjusted effect of AET omission on OS was 1.24 (95% CI: 1.02-1.51, p=0.03). Conclusions: Omission of AET in pts treated with chemotherapy for ER-low, early-stage BC is associated with significantly worse OS. These data strongly suggest that pts with ER low BC should be counseled regarding the benefit of AET and practice guidelines should recommend AET in this setting. 1. Benefield JNCI 2020. 2. Choong SABCS 2022.

Real-world duration of interruptions in imaging and endocrine therapy (ET) after pregnancy in early-stage estrogen receptor (ER) positive breast cancer (BC).

11157 Background: Pre-menopausal women with early-stage ER-positive BC often desire the option for future fertility. The POSITIVE trial demonstrated that a pause in ET to conceive is safe. However, the real-world durations of these pauses, as well as how many patients resume ET, are unclear. Additionally, there are limited data about when and if women reestablish imaging surveillance after childbirth. Methods: We generated a cohort of BC patients with a pregnancy-related ICD diagnosis from the Oncoshare registry. This registry merges EMR and California Cancer Registry data for patients treated in the Stanford Health Care Alliance which includes an academic hospital, a community hospital, and a community practice network. Included patients had ≥1 pregnancy after a diagnosis of stage 0-3 ER-positive BC. Chart review confirmed pregnancy and was used to abstract treatment information. Data are presented as unadjusted percentages or medians with interquartile ranges (IQR). Among patients without bilateral mastectomies, we compared time from delivery to first imaging (MRI or mammogram) for those who breastfed vs not and those who restarted ET vs not using the Wilcoxon rank sum test. Results: Of the 317 charts reviewed, 71 were included. Most exclusions were due to no pregnancy (46%) or ER-negative disease (25%). Year of diagnosis ranged from 1994 to 2020, with the majority (79%) from 2010 to 2020. Median age at diagnosis was 33 years (IQR 30-35). The distribution of stages was 18% in situ disease, 51% stage 1, 17% stage 2, 14% stage 3. 23% (16/71) of women never started ET, with 14 attributing this decision to desiring pregnancy. Among the 55 women who started ET, 75% received tamoxifen without ovarian suppression (OS). After 2015, use of OS became more prevalent (45% of ET), coinciding with the emergence of the SOFT/TEXT data. The median time from ET onset to a pause for pregnancy was 32 months (IQR 22-53), and the median ET pause to delivery was 23 months (IQR 14-48). We recorded 90 pregnancies resulting in 85 live births. After delivery of their first child, the median follow-up was 3.8 years (IQR 2.0-6.8). 40% of patients never restarted ET. Those who did restart did so at a median of 5 months (IQR 3-11) post-delivery. Imaging surveillance resumed for 42% (27/64) at a median of 6 months post-delivery [IQR 3-11]. Time from delivery to imaging was similar between those who restarted ET and those who did not (p=0.91), and between those who breastfeed and those who did not (p=0.42). Conclusions: These data support prior work showing that fertility concerns strongly influence adjuvant therapy choice in ER-positive BC. The ET resumption rate after pregnancy was lower in our analysis compared to the POSITIVE trial (73% vs. 40%). Only 42% of women resumed surveillance imaging. This points to clear gaps between the clinical trial population and the real-world clinical setting.

Abstract PO2-01-11: Demographic, Lifestyle, and Clinical Factors Associated with Early vs. Late Recurrence among Women with Early-Stage Estrogen Receptor-Positive Breast Cancer in the Prospective Pathways Study

Abstract Background: Although women diagnosed with early-stage estrogen receptor (ER)-positive breast cancer generally have a favorable prognosis, they face a lingering risk of late recurrence that can occur years to decades after diagnosis. Relatively little is known about the demographic, lifestyle, or clinical factors associated with the risk of late recurrence, or whether the associations differ between early vs. late recurrence. Methods: We performed a comprehensive analysis of factors related to early vs. late recurrence in early-stage ER-positive breast cancer in the Pathways Study, an established prospective cohort of women diagnosed with invasive breast cancer at Kaiser Permanente Northern California (KPNC) between 2006 and 2013. Recurrences were identified through monthly searches of the KPNC Cancer Registry, follow-up interviews with participants, and confirmation with electronic medical records. For this analysis, 2,473 women with stage I-IIB, ER-positive breast cancer were included, with ascertainment of recurrence and death through December 31, 2021. Univariate analysis and multivariable Cox regression models were used to examine the factors associated with early (&amp;lt; 5 years since diagnosis) and late (≥ 5 years since diagnosis) recurrence. Results: The median age of diagnosis was 57 (± 10) years, with 35% diagnosed before menopause. While 64% of patients self-reported as White, 16% identified as Asian, 6% Black, 12% Hispanic, and 2% other ethnicity. After a median 13.3 (range: 0.6-16.8) years of follow up, a total of 341 (13.8%) recurrences occurred, with 158 before and 181 at or after 5 years from diagnosis. Approximately a third of recurrences were local or regional and the other two thirds were distant. In univariate analysis, increasing stage and tumor grade were associated with higher risk of both early and late recurrence (p&amp;lt; 0.05). Progesterone receptor (PR) negativity was associated with only early (hazard ratio [HR]=1.49, 95% confidence interval [CI] 1.06-2.09) but not late recurrence (HR=0.90, 95% CI 0.63-1.28). In unadjusted models, receiving lumpectomy (vs. mastectomy), chemotherapy, radiation therapy, or endocrine therapy were associated with lower risk of both early and late recurrence. Among the demographic and lifestyle factors examined, postmenopausal status at diagnosis was associated with lower risk of early (HR=0.69, 95% CI 0.51-0.96) but not late recurrence (HR=1.00, 95% CI 0.73-1.36). No association was found with body mass index, socioeconomic measures (education, income, employment, marital status), smoking, alcohol intake, or physical activity assessed at the time close to diagnosis. Notably, minoritized racial/ethnic groups all had higher risk of early recurrence than White women (Asian: HR=1.76, 95% CI 1.16-2.66; Black: HR=2.33, 95% CI 1.38-3.93; Hispanic: HR=1.80, 95% CI 1.15-2.82), but no association was found with late recurrence (Asian: HR=0.99, 95% CI 0.65-1.51; Black: HR=0.80, 95% CI 0.41-1.58; Hispanic: HR=0.80, 95% CI 0.48-1.33). In multivariable Cox models adjusted for age, cancer stage, grade, PR status, surgery, radiation therapy, chemotherapy, and endocrine therapy, the trend of higher risk of early recurrence among minoritized racial/ethnic groups remained, although the association remained significant only in Black women (HR=1.89, 95% CI 1.08-3.31). Conclusion: Most histopathological features and cancer treatment modality had similar impact on early vs. late recurrence among women with early-stage ER-positive breast cancer, although PR negativity might be an adverse risk factor for early recurrence only. The findings of higher risk of early but not late recurrence among Asian, Black, and Hispanic relative to White women provide some novel data on the racial/ethnic disparities of prognosis for ER-positive breast cancer and may warrant further investigation. Citation Format: Alfredo Chua, Haiyang Sheng, Shipra Gandhi, Marilyn Kwan, Isaac Ergas, Janise Roh, Cecile Laurant, Thaer Khoury, Scarlett Gomez, Christine Ambrosone, Lawrence Kushi, Song Yao. Demographic, Lifestyle, and Clinical Factors Associated with Early vs. Late Recurrence among Women with Early-Stage Estrogen Receptor-Positive Breast Cancer in the Prospective Pathways Study [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-01-11.

Abstract PO5-01-14: Genomic risk analyses in patients with clinical low risk ER-positive HER2-negative early breast cancer developing an early metastatic event

Abstract Background: Over the past decade, there have been notable changes in the definition of risk estimation in patients with early-stage breast cancer (EBC). Specifically, within the timeframe of 2000 to 2017, following Estrogen Receptor (ER) positive and HER2-negative EBC cases were classified as low risk according to the University Hospitals of Leuven (UHL) criteria of that time: if ER H-score was &amp;gt;200: all patients with tumors N0 and Grade (G) 1, ≤pT2; or G2-3 pT1a-b; in patients ≥40 years with tumors N0 and G2 pT1c-2 or G3 pT1c; in patients ≥ 55 years with tumors N0 G3 pT2 or N1 any Grade, pT≤2. For lower H-scores, other criteria applied. However, despite undergoing endocrine therapy, a subset of these patients with clinically low-risk tumors unexpectedly experienced metastasis within five years of initial diagnosis. This unforeseen outcome may indicate potential undertreatment, as these patients did not receive adjuvant chemotherapy. We have conducted a case-cohort study of those patients with early relapse and performed the current clinical risk assessment methods and genomic risk analyses. Methods: In this study, we included patients with ER-pos, HER2-neg early-stage breast cancer diagnosed between 1-1-2000 and 31-12-2017, who were classified as low-risk tumors by UHL guidelines at that time, who were older than 35 but younger than 71 years, had an unilateral, unifocal breast tumor with tumor size up to 5 cm. These patients did not receive adjuvant chemotherapy. We selected the patients that experienced early distant recurrence, defined as distant recurrence (DR) within 5 years after the initial diagnosis. To ensure comparability for the analyses they were matched to controls for grade, menopausal status, tumor size, lymphovascular invasion, progesterone receptor status, and the year of diagnosis. For each patient, we have calculated the clinical risk score according to the criteria outlined by Mymammaprint.com, based on the modified Adjuvant Online tool used in the MINDACT trial. For the analysis, formalin-fixed paraffin-embedded (FFPE) breast tumor tissue samples were subjected to in-house validated targeted RNA-based Mammaprint(MP) analysis by NGS (MP Agendia). Results: Of the 3190 patients with EBC at UHL during the study period, 2476 patients were considered for this analysis and fitted the clinical low-risk criteria defined low-risk at UHL. Among those, only 42 or 1.7% of the eligible cohort had developed metastasis within 5 years. Tissue for MP analysis was available for 35 of these cases and for their matched control. Due to technical failure, the 1:1 matching was lost and MP results were known for 28 cases and 27 controls. The patient and tumor characteristics of both groups were comparable. In this UHL clinical low-risk group, 21/28 (75%) cases would be identified as clinical high-risk by MyMammaprint.com and 18/27 (67%) controls. We identified 13 patients (46.43%) with high genomic risk within the group with DR and 9 (33.33%) within the control group. There was no statistically significant difference (p=0.412) in the proportion of genomically high-risk patients within the group with DR compared to the control group. Conclusions: In a database of patients with EBC of whom 98% did not develop metastasis within 5 years, we observed in a small series of chemotherapy naïve patients with early DR and UHL-defined clinical low-risk tumors, that nearly half had a genomically high risk of distant metastasis. Albeit numerically higher than the matched-control group, this observation was not significant and would warrant a larger sample size and power to confirm these results. Table. Genomic versus Clinical Risk by MyMammaprint.com Citation Format: Josephine Van Cauwenberge, Hava Izci, Hans Wildiers, Sileny Han, Christine Desmedt, Giuseppe Floris, Sara Vander Borght, Ann Smeets, Ines Nevelsteen, Isabelle Vanden Bempt, Patrick Neven. Genomic risk analyses in patients with clinical low risk ER-positive HER2-negative early breast cancer developing an early metastatic event [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-01-14.

Prediction of Benefit From Adjuvant Pertuzumab by 80-Gene Signature in the APHINITY (BIG 4-11) Trial.

At the primary analysis, the APHINITY trial reported a statistically significant but modest benefit of adding pertuzumab to standard adjuvant chemotherapy plus trastuzumab in patients with histologically confirmed human epidermal growth factor receptor 2 (HER2)-positive early-stage breast cancer. This study evaluated whether the 80-gene molecular subtyping signature (80-GS) could identify patients within the APHINITY population who derive the most benefit from dual anti-HER2 therapy. In a nested case-control study design of 1,023 patients (matched event to control ratio of 3:1), the 80-GS classified breast tumors into functional luminal type, HER2 type, or basal type. Additionally, 80-GS distinguished tumor subtypes that exhibited a single-dominant functional pathway versus tumors with multiple activated pathways. The primary end point was invasive disease-free survival (IDFS). Hazard ratios (HRs) were evaluated by Cox regression. After excluding patients without appropriate consent and those with missing data, 964 patients were included. The 80-GS classified 50% (n = 479) of tumors as luminal type, 28% (n = 275) as HER2 type, and 22% (n = 209) as basal type. Most luminal-type tumors (86%) displayed a single-activated pathway, whereas 49% of HER2-type and 42% of basal-type tumors were dual activated. There was no significant difference in IDFS among different conventional 80-GS subtypes (single- and dual-activated subtypes combined). However, basal single-subtype tumors were significantly more likely to have an IDFS event (hazard ratio, 1.69 [95% CI, 1.12 to 2.54]) compared with other subtypes. HER2 single-subtype tumors displayed a trend toward greater beneficial effect on the addition of pertuzumab (hazard ratio, 0.56 [95% CI, 0.27 to 1.16]) compared with all other subtypes. The 80-GS identified subgroups of histologically confirmed HER2-positive tumors with distinct biological characteristics. Basal single-subtype tumors exhibit an inferior prognosis compared with other subgroups and may be candidates for additional therapeutic strategies. Preliminary results suggest patients with HER2-positive, genomically HER2 single-subtype tumors may particularly benefit from added pertuzumab, which warrants further investigation.

Alternative dosing regimen of exemestane in a randomized presurgical trial: the role of obesity in biomarker modulation

In a 3-arm presurgical trial, four-six weeks exemestane 25 mg three times/week (TIW) was non-inferior to 25 mg/day (QD) in suppressing circulating estradiol in postmenopausal women with ER-positive breast cancer. Since obesity may decrease exemestane efficacy, we analyzed changes in sex steroids, adipokines, Ki-67, and drug levels in relation to obesity. Postmenopausal women with early-stage ER-positive breast cancer were randomized to either exemestane 25 mg QD (n = 57), 25 mg TIW (n = 57), or 25 mg/week (QW, n = 62) for 4–6 weeks before breast surgery. Serum and tissue pre- and post-treatment biomarkers were stratified by body mass index (BMI)< or ≥30 kg/m2. Post-treatment median exemestane and 17-OH exemestane levels were 5–6 times higher in the QD arm compared to the TIW arm. For obese women, TIW maintained comparable reductions to QD in systemic estradiol levels, although the reduction in estrone was less with the TIW regimen. There was less suppression of SHBG with the TIW versus the QD dose schedule in obese women which should result in less systemic bioavailable estrogens. Metabolically, the effect of the TIW regimen was similar to the QD regimen for obese women in terms of leptin suppression and increase in the adiponectin-leptin ratio. Reduction in tissue Ki-67 was less for obese women on the TIW regimen than QD, although changes were similar for non-obese women. Our findings suggest that TIW exemestane should be explored further for primary cancer prevention in both normal weight and obese cohorts.

Analysis of the association of HER-2 low carcinomas and PAM50 assay in hormone receptor positive early-stage breast cancer.

HER2-low has emerged as a new predictive biomarker in metastatic breast cancer. However, its prognostic value in early-stage carcinomas needs to be revisited. We aimed to evaluate the association of HER2-low carcinomas with PAM50 risk groups combined with clinicopathological variables in early breast cancer. We conducted a retrospective analysis of 332 patients with early-stage breast cancer that underwent PAM50 signature analysis between 2015 and 2021at Hospital Universitario 12 de Octubre (Madrid, Spain). Clinical and pathological variables were collected from medical records. After adjusting for potential confounders, we estimated Odds Ratio (OR) and 95% confidence interval for high-risk PAM50 subgroup, comparing HER2-low versus HER2-zero carcinomas by multivariable logistic regression. P values below 0.05 were deemed statistically significant. 192 (57%) patients were classified as HER2-low carcinomas. Median follow-up was 34 months. Adjusted OR for high-risk PAM50 when comparing HER2-low versus HER2-zero carcinomas was 1.31 (95% CI: 0.75-2.30, p=0.33). The multivariable model detected significant associations for Ki-67% (≥20% vs. <20%: OR=4.03, 95% CI: 2.15-7.56, p<0.001), T staging category (T2/T3 vs. T1: OR=3.44, 95% CI: 1.96-6.04, p<0.001), progesterone receptor (PR≥20% vs. <20%: OR=0.44, 95% CI: 0.23-0.83, p=0.01), nodal staging category (N+ vs. N0: OR=3.8, 95% CI: 1.89-7.62, p<0.001) and histological grade (grade 2 vs. 1: OR=2.41, 95% CI: 1.01-5.73, p=0.04; grade 3 vs 1: OR=5.40, 95%CI: 1.98-14.60, p=0.001). In this early-stage breast cancer cohort, HER2-low was not associated with a high-risk PAM50 compared to HER2-zero carcinomas. Ki-67≥20%, T2/T3, histological grade 2/3, N+ and PR<20% were significantly associated to a high-risk PAM50.

The impact of the 4R Oncology model on OncotypeDx turnaround time.

531 Background: The OncotypeDx genomic assay has been widely used to predict recurrence in those with early-stage ER positive breast cancer to determine whether adjuvant chemotherapy is beneficial. Receiving OncotypeDx results in a timely manner prior to medical oncology appointment is critical to inform adjuvant therapy decisions. In this quality improvement project, we implemented a care delivery optimization for patients with breast cancer receiving OncotypeDx assays in an integrated healthcare system. The optimization was conducted as part of implementing the 4R Oncology model (Right Info / Right Care / Right Patient / Right Time), a novel care model that aims to optimize patient-centric care planning, team-based delivery and patient self-management. Herein, we assess the impact of implementing this model on improving OncotypeDx turnaround time. Methods: We examined two patient groups with newly diagnosed early-stage ER positive breast cancer who attended a multidisciplinary clinic and underwent surgery at a single medical center. The historical control (HC) group received care pre-4R implementation, from January 2019 through June 2020, while the 4R Intervention group received care from July 2020 to December 2021. The OncotypeDx-related care optimization was a team effort of 5 medical specialties that involved establishing an OncotypeDx reflex testing practice, updating workflows, working with a testing company to streamline the process and implementing a method to align result timing with scheduling medical oncology appointments. Bivariate analyses were used to compare the HC and 4R groups on demographic characteristics and OncotypeDx turnaround time. Results: Within the 4R group (N = 208), 72 (34.6%) patients received OncotypeDx and 89 (32.5%) patients from the HC cohort (N = 274) received OncotypeDx. The groups were balanced by median age at time of multidisciplinary clinic visit (HC: 59 years vs 4R: 60 years), female gender (HC: 99.6% vs 4R: 99.5%), race, combined race and ethnicity, language spoken, Charlson Comorbidity Index and tumor characteristics. The average turnaround time from surgery date to delivery of OncotypeDx results was significantly reduced in the 4R cohort (19.4 days) compared to that of the HC cohort (23.1 days), a difference of 3.8 days, p = 0.004. The availability of OncotypeDx results by the first medical oncology visit after surgery increased from 40% in the HC cohort to 69% in the 4R cohort, p = 0.0003, helping optimize the transition to adjuvant therapy for the appropriate population. Conclusions: The implementation of the 4R Oncology model within an integrated healthcare system significantly reduced turnaround time for patients with breast cancer awaiting OncotypeDx results, improving patient-centric care and enabling informed discussions at medical oncology visits. The 4R Oncology model is an effective method to optimize delivery of time-sensitive care.

Impact of HER2 low expression in the Oncotype DX RS in patients with operable hormone receptor positive early stage breast cancer.

575 Background: Two thirds of breast carcinomas are human epidermal growth factor receptor 2 (HER2) low. To date, it is still unclear whether hormone receptor (HR) positive HER2 low tumors represent a distinct biological subtype. HER2 low status is not considered an independent predictive factor for benefit from adjuvant chemotherapy in HR positive early breast cancer. We aim to investigate the impact of HER2 low expression on the established predictive biomarker Oncotype DX RS in a cohort of patients with HR positive HER2 negative early breast cancer. Methods: Retrospective study of patients with stage I-III HR positive HER2 negative breast cancer treated with upfront surgery between 2019-2022 at the Weill Cornell Breast Center and for whom Oncotype DX RS test was available. Patients were grouped to HER2-0 (immunohistochemistry (IHC) score of 0) or HER2 low (IHC score of 1+ or, 2+ with non-amplified in situ hybridization) expression. Clinicopathological characteristics and Oncotype DX RS were compared across the different categories of HER2 expression. Results: Of 509 patients included, 37% and 63% were grouped as HER2-0 and HER2 low, respectively. Median age at diagnosis was 61 years [IQR 50-69]. Sixty-eight percent of patients were postmenopausal. Stage I, II and III corresponded to 76%, 23% and 1% of patients, respectively. Seven percent of patients had nodal involvement. Ductal carcinoma was the most common histological type (75%) followed by lobular carcinoma (17%). Most tumors had low-intermediate histological grade (81%) with a median Ki-67 of 10% [IQR 5-15]. No significant difference was observed in clinicopathological characteristics between the HER2-0 and HER2 low groups. The overall median Oncotype DX RS was 16 [IQR 11-21]. The median Oncotype DX RS based on a HER2 expression of 0, 1+ and 2+ was 15, 17 and 17, respectively. There was no statistically significant difference between the Oncotype DX RS score and HER2 expression, when comparing HER2-0 to HER2 low (p = 0.578), HER2-0 to HER2-1+ (p = 0.775) and HER2-0 to HER2-2+ (p = 0.157). In the pre-menopausal and lobular carcinoma subgroups, the median Oncotype DX RS was 15 [IQR 9-21] and 17 [IQR 12-22], respectively; and there was no statistically significant difference between the Oncotype DX RS score and HER2 expression (p &gt; 0.05). Post-surgery, 87%, 66% and 13% of patients received endocrine therapy, chemotherapy and radiation therapy, respectively. Median follow up time was 16 months [IQR 8-34]. Disease recurrence was documented in 9 (2%) patients. Conclusions: In this study, we found no differences in the Oncotype DX RS and the prognostic pathological features between the HER2-0 and HER2 low groups which is in line with previous retrospective studies. Survival analysis was limited by the median follow up. Further studies on the understanding of the biology of HER2-low and its clinical implications in early breast cancer are needed.

Prognostic impact of adjuvant endocrine therapy for estrogen receptor-positive and HER2-negative T1a/bN0M0 breast cancer.

538 Background: Adjuvant endocrine therapy (ET) is the standard of care for Estrogen Receptor (ER)-positive early-stage breast cancer. However, many patients suffer from adverse events associated with ET. The prognosis of patients with T1a/bN0 breast cancer with ER-positive and human epidermal growth factor 2 (HER2)-negative is excellent, and it is not clear whether adjuvant ET should be recommended. Here we evaluate the effect of adjuvant ET for ER-positive and HER2-negative T1a/bN0M0 breast cancer. Methods: This study was a multicenter, retrospective cohort study that evaluated adjuvant ET for patients with ER-positive and HER2-negative T1a/bN0M0 breast cancer. Patients who underwent surgery between 2008 and 2012 in 47 institutions of the Japan Clinical Oncology Group (JCOG) breast cancer group were eligible. We analyzed the cumulative incidence of distant metastasis as primary endpoint using the Gray test model and time to event endpoints (distant disease free survival and overall survival) using log-rank test between patients treated with and without adjuvant ET. We also used Gray test model for the analysis of the cumulative incidence of ipsilateral and contralateral breast cancer. Predictive factors were assessed using the Fine-Gray model and the Cox proportional hazards model. Results: The median follow-up period was 9.2 years. Of 4758 eligible patients (1202 T1a [25.3%] and 3556 T1b [74.7%] diseases), 3991 (83.9%) received adjuvant ET. The 9-year cumulative incidence of distant metastasis was 1.5% with ET and 2.6% without ET (adjusted subdistribution hazard ratio [sHR], 0.54; 95% CI, 0.32-0.93). In the multivariate analysis, the independent risk factors of distant metastasis were no ET, mastectomy, high grade, and lymphatic invasion. The 9-year overall survival was 97.0% and 94.4% (HR, 0.54; 95% CI, 0.38-0.77). Adjuvant ET reduced the incidence of ipsilateral and contralateral breast cancer (9-year rates; 1.1% vs 6.9%; sHR, 0.17; 95% CI 0.11-0.28, and 1.9% vs 5.2%; sHR, 0.33; 95% CI, 0.22-0.49). Conclusions: Adjuvant endocrine therapy significantly reduces distant metastases, however the absolute difference is small for ER-positive and HER2-negative T1a/bN0M0 breast cancer. Furthermore, it reduced ipsilateral and contralateral breast cancer as well. Shared decision making regarding the omission of adjuvant endocrine therapy is crucial, especially in patients with low risk of distant metastasis.

Abstract OT2-20-01: Neoadjuvant survivin immunotherapy maveropepimut-S (MVP-S) to increase Th1 immune response in Ki67-high hormone receptor positive (HR+) early-stage breast cancer

Abstract Background: HR+ early stage breast cancer (ESBC) is associated with suboptimal pathologic complete response rate (pCR, ~10%) following neoadjuvant cytotoxic chemotherapy. Neoadjuvant endocrine therapy with aromatase inhibitors (AI) may serve as an effective alternative as gauged using the surrogate Ki67 cell proliferation histologic marker. Patients with poor Ki67 response (defined as Ki67&amp;gt;10%) following neoadjuvant AI exhibit poor prognosis and therapeutic resistance to both endocrine therapy and chemotherapy. In a genomic analysis of Ki67-high HR+ tumors, we identified 8-fold upregulation of BIRC5 (survivin), a gene that regulates apoptosis and the cell cycle and is associated with poor clinical outcome. Maveropepimut-S (MVP-S) leverages the non-aqueous, lipid-based DPX delivery platform to educate a specific and persistent T cell-based immune response to 5 HLA-restricted peptides from Survivin. Treatment with MVP-S and intermittent, low-dose cyclophosphamide (CPA) has shown to increase tumor infiltration of survivin-specific T cells. Previous clinical trials have shown that MVP-S is well-tolerated, immunogenic, and could lead to clinical response in several cancer indications. Further exploration of the regimen in breast cancer could extend the application of this immunotherapy for the unmet medical need of improving clinical response in high ki67 HR+ ESBC prior to surgery. Trial Design: NCT04895761 is phase I trial evaluating the safety and immunologic effects of neoadjuvant MVP-S plus letrozole (arm A, n=6), with/without tumor-directed MR-guided radiotherapy (arm B, n=6), or intermittent low-dose cyclophosphamide (CPA, arm C, n=6). Postmenopausal patients with T1c+ HR+HER2- breast cancer with Ki67&amp;gt;10% will receive two doses of MVP-S and 7 weeks of neoadjuvant letrozole prior to surgery (all arms), arm B will be treated additionally with concurrent 10Gy x 2 tumor boost radiation to facilitate immunogenic cell death, and arm C (n=6) will be treated additionally with intermittent low-dose CPA (50mg BID) to facilitate regulatory T cell depletion. Specific Aims: The primary objective is safety. Biomarker objectives are to evaluate for each treatment arm: 1) systemic type I survivin-specific immune response, as measured by IFN-γ ELISPOT; 2) changes in immune environment by GeoMx digital spatial genomic profiling; 3) and changes in tumor infiltrating lymphocytes (TILs) and Ki67. These data will be used to identify the most immunogenic MVP-S combination therapy for study in phase II trial powered to assess clinical outcome (pCR). Accrual: 3 of 6 patients in the MVP-S+ letrozole arm have been enrolled. Arm B and C will enroll after completion of arm A. Citation Format: Sasha E. Stanton, Lisa D. MacDonald, Stephan Fiset, Staci Mellinger, Nicole Moxon, Heather Hirsch, Tracy L. Kelly, Kristina H. Young, David B. Page. Neoadjuvant survivin immunotherapy maveropepimut-S (MVP-S) to increase Th1 immune response in Ki67-high hormone receptor positive (HR+) early-stage breast cancer. [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT2-20-01.

Abstract P2-02-04: De-escalation of bone-targeted treatment: Does the number of 6-monthly adjuvant zoledronate infusions received affect treatment efficacy for early breast cancer? A sub-study of ABCSG-12

Abstract Background: The results of the Early Breast Cancer Trialist Group (EBCTCG) meta-analysis (Lancet 2015) led to the widespread adoption of bisphosphonates as adjuvant therapy for postmenopausal early-stage breast cancer (EBC). Despite evaluating multiple bisphosphonate agents and regimens, there was no signal of varying efficacy with different agents, routes of administration or dose/dose intensity. We evaluated the question of treatment de-escalation using long-term outcome data from the prospective randomized ABCSG-12 trial. Patients and methods: Between 1999 and 2006, ABCSG-12 accrued 1803 patients with hormone-receptor positive EBC on ovarian function suppression for three years that were randomized to receive 4 mg zoledronic acid 6-monthly or not (and tamoxifen or anastrozole, in a 2:2 factorial design). In the current retrospective study, we evaluated whether the number of zoledronate infusions actually received had an impact on breast cancer-specific and fragility fracture outcomes. Based on the results of the EBCTCG meta-analysis, we hypothesized that amongst patients who receive less infusions than the planned seven zoledronate infusion in this trial, the number of infusions has no differential effect on these outcomes. Time to event endpoints were analyzed with Cox models and Kaplan Meier curves starting from a 3-year landmark. BMD subset analyses were restricted to patients who participated in the BMD sub-study with available BMD data. Results: 725 patients who received at least one zoledronate infusion were included in the time-to-event-analysis. There was no statistically significant difference in disease-free survival (adjusted HR 0.83, 95% CI 0.48–1.44, p=0.51) or overall survival (HR 0.97, 95% 0.30-3.11, p=0.96) in patients who received ≤6 zoledronate infusions (n=170) compared to those who received ≥7 zoledronate infusions (n=555) (adjusted HR 0.83, 95% CI 0.48 – 1.44, p=0.51). Both subgroups show stable lumbar spine and total hip BMD measurements across the five years. Conclusions: Comparable to the metastatic bone disease and fragility fracture settings, there was no evidence observed to indicate that a reduced number of zoledronate infusions is associated with reduced adjuvant efficacy. Further studies to define optimal regimens of adjuvant bone-targeted therapies (prospective evaluation of “how-low-can-you-go”) are required. Table 1: Multivariate Cox Regression: DFS and OS Table 2: BMD and percent change from baseline at the total hip and lumbar spine (L1-L4) over 60 months Citation Format: Ana-Alicia Beltran-Bless, Mark Clemons, Christian Fesl, Dominik Hlauschek, Lidija Soelkner, Gregory R. Pond, Lisa Vandermeer, Richard Greil, Marija Balic, Vesna Bjelic-Radisic, Christian F. Singer, Guenther Steger, Ruth Helfgott, Daniel Egle, Simon P. Gampenrieder, Stephanie Kacerovsky-Strobl, Christoph Suppan, Magdalena Ritter, Gabriel Rinnerthaler, Georg Pfeiler, Hannes Fohler, John Hilton, Michael Gnant. De-escalation of bone-targeted treatment: Does the number of 6-monthly adjuvant zoledronate infusions received affect treatment efficacy for early breast cancer? A sub-study of ABCSG-12 [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-02-04.

Cost-Effectiveness Analysis of Ultra-Hypofractionated Whole Breast Radiation Therapy Alone Versus Hormone Therapy Alone or Combined Treatment for Low-Risk ER-Positive Early Stage Breast Cancer in Women Aged 65 Years and Older

The optimal management of early-stage, low-risk, hormone-positive breast cancer in older women remains controversial. Recent trials have shown that 5-fraction ultrahypofractionated whole-breast irradiation (U-WBI) has similar outcomes to longer courses, reducing the cost and inconvenience of treatment. We performed a cost-utility analysis to compare U-WBI to hormone therapy alone or their combination. We simulated 3 different treatment approaches for women age 65 years or older with pT1-2N0 ER-positive invasive ductal carcinoma treated with lumpectomy with negative margins using a Markov microsimulation model. The strategies were U-WBI performed with a 3-dimensional conformal technique over 5 fractions without a boost ("radiation therapy [RT] alone"), adjuvant hormone therapy (anastrozole for 5 years) without RT ("aromatase-inhibitor [AI] alone"), or the combination of the 2. The combination strategy was calibrated to match trial results, and the relative effectiveness of the RT alone and AI alone strategies were inferred from previous randomized trials. The primary endpoint was the cost-effectiveness of the 3 strategies over a lifetime horizon as measured by the incremental cost-effectiveness ratio (ICER), with a value of $100,000/quality-adjusted life-year deemed "cost-effective." The model results compared with the prespecified target outcomes. On average, RT alone was the least expensive strategy ($14,775), with AI alone slightly more ($14,998), and combination therapy the costliest ($19,802). RT alone dominated AI alone (the incremental cost-effectiveness ratio [ICER] -$5089). Combination therapy, compared with RT alone, was slightly more expensive than our definition of cost-effective (ICER $113,468) but was cost-effective compared with AI alone (ICER $54,451). Probabilistic sensitivity analysis demonstrated RT alone to be cost-effective in 50% of trials, with combination therapy in 36% and AI alone in 14%. U-WBI alone appears the more cost-effective de-escalation strategy for these low-risk patients, compared with AI alone. Combining U-WBI and AI appears more costly but may be preferred by some patients.

Optimizing adjuvant and post-neoadjuvant therapy in HER2-positive early breast cancer

Introduction Treatment advances have improved outcomes in human epidermal growth factor receptor 2 (HER2)-positive early-stage breast cancer (eBC) but certain patients remain at high risk of recurrence. Neoadjuvant therapy (NAT) has comparable outcomes to adjuvant therapy with the advantage of surgical down-staging, response assessment, informing prognosis, and tailoring adjuvant treatment. Thus, the standard of care for the majority of HER2-positive eBC has become a combination of chemotherapy and HER2-targeted agents given in the neoadjuvant setting. Areas covered Mounting evidence suggests that pathologic complete response after NAT translates to a favorable long-term prognosis. The efficacy and tolerability of post-NAT are key, particularly for patients with residual disease. This is demonstrated, for example, by the use of trastuzumab emtansine in the appropriate clinical setting and various new drugs under investigation. This review summarizes the current clinical management and exciting future directions to optimize outcomes in HER2-positive eBC. Expert opinion Targeted therapies such as trastuzumab deruxtecan, tucatinib, and immunotherapy have demonstrated impressive responses in metastatic breast cancer, including CNS disease. Incorporating these agents in the post-neoadjuvant space may improve the prognosis of HER2-positive eBC. Future research should prioritize the identification of biomarkers that personalize treatments to achieve maximum benefit and less toxicity.

Prediction of Cardiac Toxicity by Measurement of Coronary Artery Calcium Scoring Method Using Chest Computed Tomography in Early Breast Cancer Patients Treated with Trastuzumab

Background: In human epidermal growth factor receptor 2 (HER2)-positive early stage breast cancer, prediction of trastuzumab-related cardiac toxicity remains a challenge. The coronary calcium artery (CAC) reflects the total coronary plaque burden, which predicts the risk of atherosclerosis. We investigated the prediction of left ventricular ejection fraction (LVEF) decline in breast cancer according to CAC scores. Methods: A total of 347 patients were enrolled from Seoul St Mary’s Hospital between January 2010 and December 2019. Chest computed tomography (CT) was performed at a single tertiary center. Patients who received trastuzumab for HER2-positive early breast cancer were included in this study. Results: Of the 347 patients, 312 and 35 had CAC scores of 0 and ≥1, respectively. The CAC ≥1 group was associated with older age, body mass index, and receipt of left breast irradiation. The CAC ≥1 group was significantly associated with LVEF decline (absolute value, ≤50%) (hazard ratio [HR] 12.038, 95% confidence interval [CI] 2.845–50.937, p = 0.001), LVEF decline (absolute value, ≤55%) (HR 4.439, 95% CI: 1.787–11.028, p = 0.001), and decline in LVEF of ≥10% points compared with baseline echography (HR 5.083, 95% CI: 1.658–15.582, p = 0.004). Even after adjusting for other clinical factors, CAC ≥1 remained a significant predictor of decreased LVEF. Conclusion: Our findings suggest that the CAC score is a significant predictor of cardiac toxicity following trastuzumab treatment in HER2-positive breast cancer. Therefore, CAC measurement could reduce cardiac toxicity by distinguishing patients at high risk for trastuzumab.

Effect of Aromatase Inhibitors on Serum Calprotectin Levels in an Animal Experimental Model: Trial.

Utilizing an experimental animal model, we investigated the correlation between aromatase inhibitors (AIs) (anastrozole and letrozole) and Calprotectin levels. AIs have demonstrated superior efficacy when used as adjuvant endocrine therapy or monotherapy for postmenopausal patients with hormone receptor (HR)-positive early-stage breast cancer, although various side effects have been recorded. Fifty-five adult female Wistar rats were randomized and assigned into four groups. The control group received no intervention. The other three groups were subjected to ovariectomy, and serum Calprotectin levels were measured at baseline, 2, and 4 months. In addition, glucose, total cholesterol, very low-density lipoprotein- (VLDL-) cholesterol, low-density lipoprotein (LDL-) cholesterol, high-density lipoprotein- (HDL-) cholesterol, and triglyceride levels were measured. Histological analysis of liver tissue was carried out following rats' euthanasia. Aromatase inhibitors (anastrozole and letrozole) affect calprotectin levels in ovariectomized rats. Calprotectin, a marker of inflammation, was found to be affected by the use of the inhibitors. The potential of hepatotoxicity can be examined by assessing the elevation of inflammation markers such as Calprotectin, which is an indicator that should be strictly taken into consideration when administering aromatase inhibitors as treatment.

Cost-Effectiveness Analysis of Ultra-Short Whole Breast Radiation Therapy Alone vs. Endocrine Only or Combined Treatment for Low-Risk ER-Positive Early-Stage Breast Cancer in Women Age 70 and Older

<h3>Purpose/Objective(s)</h3> The optimal management of early-stage, low-risk, hormone-positive breast cancer in women age 70 and older remains controversial. Recent trials have shown whole-breast radiation courses of only 5 fractions have similar outcome as longer courses, reducing the cost and inconvenience of treatment. We therefore performed a cost-utility analysis to compare ultra-short whole breast irradiation (U-WBI) to endocrine therapy (ET) alone and to combined ET and U-WBI. <h3>Materials/Methods</h3> We simulated the cost-effectiveness and acute and late effects of different treatment approaches for women age 70 years or older with pT1-2N0 ER-positive invasive ductal carcinoma treated with lumpectomy with negative margins using a Markov microsimulation model. The strategies were: U-WBI performed with a 3D technique over 5 fractions without a boost ("RT Alone"), adjuvant ET (anastrozole for 5 years) without RT ("AI Alone"), or the combination of the two. The FAST-Forward trial served as the basis for this analysis. The combination strategy was calibrated to match the trial results. The relative effectiveness of the RT Alone and AI Alone strategies were inferred from historical randomized trials. Costs were obtained from 2022 Medicare rates. Utilities and other costs were obtained from the literature. The primary endpoint was the cost-effectiveness of the 3 strategies over a 10-year horizon as measured by the incremental cost-effectiveness ratio (ICER), with a value of $100,000/QALY deemed "cost-effective". Deterministic and probabilistic sensitivity analyses were performed to evaluate parameter uncertainty. <h3>Results</h3> The model was validated using 500,000 simulated patients, each treated with the 3 strategies. The model results agreed well with the pre-specified target outcomes. On average, RT Alone was the least expensive strategy ($15,200), with AI Alone slightly more expensive, ($16,761), and combination therapy the most costly ($20,416). The most effective strategy was the combination (9.497 QALY), with small differences between RT Alone (9.453) and AI Alone (9.420). Therefore, the AI Alone strategy was more costly and less effective than RT Alone (dominated), and the combination therapy was slightly more expensive than the usual definition of "cost-effective" (ICER $117,721 relative to RT Alone). Probabilistic sensitivity analysis demonstrated RT Alone to be cost-effective in 52% of trials, with combination in 35% and AI Alone in 13%. <h3>Conclusion</h3> U-WBI without ET represents a cost-effective strategy for low-risk women in the United States, with slightly higher QALY outcome compared to AI Alone. Combination therapy improves outcome very modestly. Hence, many patients may prefer RT Alone in order to avoid the possible side effects of ET. Discussion of these options must account for patients' weighing of these issues.

161P MammaPrint and BluePrint diagnostic tests can be robustly assessed on Whole-Transcriptome NGS platform

161P MammaPrint and BluePrint diagnostic tests can be robustly assessed on Whole-Transcriptome NGS platform