Lower Breast Cancer Research Articles

Comparative morphology of tumour microenvironment in claudin-low and claudin-high breast cancers

BackgroundClaudin-low breast cancers (BCs) exhibit more aggressive behaviour compared to claudin-high types. Claudin-low BCs are often characterized by features such as a higher grade, enrichment of stemness characteristics, and a propensity for metastasis. Tumour microenvironment (TME) defined as the intricate network of surrounding cells, blood vessels, and extracellular matrix components influences the behaviour of cancer cells within the breast tissue. Understanding the TME is crucial for comprehending the aggressive characteristics of claudin-low BCs. MethodsIn this study, we have studied the morphology of immune and non-immune TME using Haematoxylin and eosin (H&E)-stained slides of 15 claudin-low and 12 claudin-high tissue samples of BC. ResultsTME of claudin-low BCs was observed to have a significantly higher frequency of retraction clefts (66.6 %; n = 10/15), immature desmoplastic response (40 %; n = 6/15), higher stromal cellularity (60 %; n = 9/15); and fibroblastic proliferation (53.3 %; n = 8/15) with a low prevalence of elastosis (66.6 %; n = 10/15). The immune microenvironment revealed a higher frequency of total (80 %; n = 12/15) as well as stromal (86.67 %; n = 13/15) and intra-tumoural TILs (60 %; n = 9/15) in them. ConclusionThe above morphology-based study revealed that claudin-low tumours have unique immune and non-immune TME as compared to claudin-high tumours. Future studies exploring the molecular correlates of each of the above morphological features can help in identifying novel therapeutic targets for the treatment of claudin-low BCs.

Michael Addition-Based Neoadjuvant for Enhanced Cancer Immunotherapy.

Cancer immunotherapy suffers from inefficient antigen presentation owing to the limited endocytosis of antigen by dendritic cells (DCs) and dysfunction of DCs in the immunosuppressive tumor microenvironment (ITME). Here, we revealed that cinnamaldehyde-grafted polyethylenimine (PC) held the potential to serve as a neoadjuvant to modulate the above processes and thus potentiate immune responses. The PC neoadjuvant could capture the tumor antigen generated during chemotherapy to enhance the crosstalk between the antigen and DCs. Then, it depleted the intracellular glutathione by the in situ Michael addition reaction, which not only activated the NOD-, LRR-, and pyrin domain-containing 3 (NLRP3) pathway to promote DCs maturation but also triggered the antigen release. As a result, it significantly augmented antigen presentation with a 46% ratio of DCs maturation and a 53% ratio of CD8+ T cell infiltration in low immunogenic murine breast cancer.

Mammography Screening Preferences Among Screening-Eligible Women in Their 40s : A National U.S. Survey.

The U.S. Preventive Services Task Force (USPSTF) recently changed its recommendation for mammography screening from informed decision making to biennial screening for women aged 40 to 49 years. Although many women welcome this change, some may prefer not to be screened at age 40 years. To conduct a national probability-based U.S. survey to investigate breast cancer screening preferences among women aged 39 to 49 years. Pre-post survey with a breast cancer screening decision aid (DA) intervention. (ClinicalTrials.gov: NCT05376241). Online national U.S. survey. 495 women aged 39 to 49 years without a history of breast cancer or a known BRCA1/2 gene mutation. A mammography screening DA providing information about screening benefits and harms and a personalized breast cancer risk estimate. Screening preferences (assessed before and after the DA), 10-year Gail model risk estimate, and whether the information was surprising and different from past messages. Before viewing the DA, 27.0% of participants preferred to delay screening (vs. having mammography at their current age), compared with 38.5% after the DA. There was no increase in the number never wanting mammography (5.4% before the DA vs. 4.3% after the DA). Participants who preferred to delay screening had lower breast cancer risk than those who preferred not to delay. The information about overdiagnosis was surprising for 37.4% of participants versus 27.2% and 22.9% for information about false-positive results and screening benefits, respectively. Respondent preferences may have been influenced by the then-current USPSTF guideline. There are women in their 40s who would prefer to have mammography at an older age, especially after being informed of the benefits and harms of screening. Women who wanted to delay screening were at lower breast cancer risk than women who wanted screening at their current age. Many found information about the benefits and harms of mammography surprising. National Cancer Institute.

Development of a deep-learning model tailored for HER2 detection in breast cancer to aid pathologists in interpreting HER2-low cases.

Over 50% of breast cancer cases are "Human epidermal growth factor receptor 2 (HER2) low breast cancer (BC)", characterized by HER2 immunohistochemistry (IHC) scores of 1+ or 2+ alongside no amplification on fluorescence in situ hybridization (FISH) testing. The development of new anti-HER2 antibody-drug conjugates (ADCs) for treating HER2-low breast cancers illustrates the importance of accurately assessing HER2 status, particularly HER2-low breast cancer. In this study we evaluated the performance of a deep-learning (DL) model for the assessment of HER2, including an assessment of the causes of discordances of HER2-Null between a pathologist and the DL model. We specifically focussed on aligning the DL model rules with the ASCO/CAP guidelines, including stained cells' staining intensity and completeness of membrane staining. We trained a DL model on a multicentric cohort of breast cancer cases with HER2-IHC scores (n = 299). The model was validated on two independent multicentric validation cohorts (n = 369 and n = 92), with all cases reviewed by three senior breast pathologists. All cases underwent a thorough review by three senior breast pathologists, with the ground truth determined by a majority consensus on the final HER2 score among the pathologists. In total, 760 breast cancer cases were utilized throughout the training and validation phases of the study. The model's concordance with the ground truth (ICC = 0.77 [0.68-0.83]; Fisher P = 1.32e-10) is higher than the average agreement among the three senior pathologists (ICC = 0.45 [0.17-0.65]; Fisher P = 2e-3). In the two validation cohorts, the DL model identifies 95% [93% - 98%] and 97% [91% - 100%] of HER2-low and HER2-positive tumours, respectively. Discordant results were characterized by morphological features such as extended fibrosis, a high number of tumour-infiltrating lymphocytes, and necrosis, whilst some artefacts such as nonspecific background cytoplasmic stain in the cytoplasm of tumour cells also cause discrepancy. Deep learning can support pathologists' interpretation of difficult HER2-low cases. Morphological variables and some specific artefacts can cause discrepant HER2-scores between the pathologist and the DL model.

Detection of Cardiotoxicity Using Right Ventricular Free Wall Longitudinal Strain in Low Cardiovascular Risk Breast Cancer Patients Receiving Low-Dose Anthracycline Treatment.

Objective Breast cancer patients who receive chemotherapy may develop cancer therapy-related cardiovascular toxicity, particularly if they have pre-existing cardiovascular risk factors. Notably, right ventricle dysfunction may manifest before the left ventricle. Our study aims to compare conventional echocardiography with global longitudinal strain (GLS) in low cardiovascular risk patients on low-dose anthracycline, focusing on early cardiotoxicity detection. Additionally, we explore the predictive role of right ventricular free wall longitudinal strain (RVFWLS) in cardiotoxicity. Methods In a recent study, 28 women with low cardiovascular risk who underwent low-dose anthracycline chemotherapy for breast cancer were assessed for cardiac function using two-dimensional echocardiography and speckle-tracking echocardiography. The measurements included left ventricular ejection fraction (LVEF), right ventricular systolic function (RVS'), tricuspid annular plane systolic excursion (TAPSE), left ventricular global longitudinal strain (LVGLS), and RVFWLS. All patients had normal LVEF at the beginning of the study. Cardiotoxicity was defined as a new decrease in LVEF by 10% or below 53% and/or changes in LVGLS/RVFWLS by 15%. Results In our study, no significant changes were observed in the LVEF following chemotherapy treatment. The LVEF values remained stable, changing slightly from 63 ± 3.7 to 65.0 ± 3.4, with a t-test value of 1.790 and a p-value of 0.079. Similarly, the analysis found no significant changes in RVS' and TAPSE values following chemotherapy treatment. However, significant changes were observed in strain measurements. LVGLS decreased from -21.2 ± 2.1 to -18.6 ± 2.6 (t-test = -4.116; df = 54, p=0.001), and RVFWLS decreased from -25.2 ± 2.9 to -21.4 ± 4.4 (t-test = -3.82; df = 54, p=0.001). Notably, 35% of participants showed changes in RVFWLS greater than 15%, whereas LVGLS changed by less than 15%. This indicates that RVFWLS is more sensitive to the treatment compared to LVGLS. Conclusions The study results indicate that during the initial phases of chemotherapy treatment in low cardiovascular risk patients, early changes in strain measures reveal subclinical cardiotoxicity. This suggests that GLS measurements are more effective at detecting early signs of myocardial damage and potential deterioration in cardiac function than traditional echocardiographic parameters. Additionally, it is noteworthy that RVFWLS exhibits greater sensitivity to these changes, regardless of the chemotherapy dosage and regimen.

Performance evaluation of ML models for preoperative prediction of HER2-low BC based on CE-CBBCT radiomic features: A prospective study.

To explore the value of machine learning (ML) models based on contrast-enhanced cone-beam breast computed tomography (CE-CBBCT) radiomics features for the preoperative prediction of human epidermal growth factor receptor 2 (HER2)-low expression breast cancer (BC). Fifty-six patients with HER2-negative invasive BC who underwent preoperative CE-CBBCT were prospectively analyzed. Patients were randomly divided into training and validation cohorts at approximately 7:3. A total of 1046 quantitative radiomic features were extracted from CE-CBBCT images and normalized using z-scores. The Pearson correlation coefficient and recursive feature elimination were used to identify the optimal features. Six ML models were constructed based on the selected features: linear discriminant analysis (LDA), random forest (RF), support vector machine (SVM), logistic regression (LR), AdaBoost (AB), and decision tree (DT). To evaluate the performance of these models, receiver operating characteristic curves and area under the curve (AUC) were used. Seven features were selected as the optimal features for constructing the ML models. In the training cohort, the AUC values for SVM, LDA, RF, LR, AB, and DT were 0.984, 0.981, 1.000, 0.970, 1.000, and 1.000, respectively. In the validation cohort, the AUC values for the SVM, LDA, RF, LR, AB, and DT were 0.859, 0.880, 0.781, 0.880, 0.750, and 0.713, respectively. Among all ML models, the LDA and LR models demonstrated the best performance. The DeLong test showed that there were no significant differences among the receiver operating characteristic curves in all ML models in the training cohort (P > .05); however, in the validation cohort, the DeLong test showed that the differences between the AUCs of LDA and RF, AB, and DT were statistically significant (P = .037, .003, .046). The AUCs of LR and RF, AB, and DT were statistically significant (P = .023, .005, .030). Nevertheless, no statistically significant differences were observed when compared to the other ML models. ML models based on CE-CBBCT radiomics features achieved excellent performance in the preoperative prediction of HER2-low BC and could potentially serve as an effective tool to assist in precise and personalized targeted therapy.

Trastuzumab deruxtecan (T-DXd) vs physician’s choice of chemotherapy (TPC) in patients (pts) with hormone receptor-positive (HR+), human epidermal growth factor receptor 2 (HER2)-low or HER2-ultralow metastatic breast cancer (mBC) with prior endocrine therapy (ET): Primary results from DESTINY-Breast06 (DB-06).

LBA1000 Background: T-DXd is approved for HER2-low (IHC 1+ or 2+/ISH-negative) mBC after ≥1 line of chemotherapy (CT). DB-06 (NCT04494425) evaluated T-DXd in pts with HER2-low or -ultralow (IHC 0 with membrane staining), HR+ mBC after disease progression (PD) on endocrine-based therapy and no prior CT for mBC. Methods: Pts with HER2-low or -ultralow, HR+ mBC were randomized 1:1 to T-DXd 5.4 mg/kg or TPC. Pts had no prior CT for mBC, with ≥2 lines of ET for mBC, or 1 line of ET for mBC if PD occurred ≤24 months (mo) of adjuvant ET or ≤6 mo of ET+CDK4/6i for mBC. Primary endpoint was progression-free survival (PFS) by blinded independent central review (BICR) in HER2-low. Key secondary endpoints were PFS in intent-to-treat (ITT = HER2-low and -ultralow) and overall survival (OS). Other endpoints included objective response rate (ORR) and safety. Results: As of Mar 18, 2024, 866 pts (HER2-low, n=713; HER2-ultralow, n=153) were randomized; 90.4% had prior CDK4/6i. TPC group pts were selected for capecitabine (59.8%), nab-paclitaxel (24.4%) or paclitaxel (15.8%). T-DXd significantly improved PFS vs TPC in HER2-low (HR, 0.62 [95% CI 0.51, 0.74], P<0.0001; median, 13.2 vs 8.1 mo). ITT and HER2-ultralow results were consistent with HER2-low (Table). Median treatment duration was 11.0 mo (T-DXd) vs 5.6 mo (TPC). OS was immature at first interim analysis (HER2-low HR, 0.83 [95% CI 0.66, 1.05], P=0.1181; median follow up, 18.6 mo). Grade (Gr) ≥3 drug-related adverse events occurred in 40.6% (T-DXd) vs 31.4% (TPC). Adjudicated interstitial lung disease / pneumonitis occurred in 49 (11.3%; 0.7% Gr 3/4, 0.7% Gr 5) vs 1 (0.2% Gr 2) pts receiving T-DXd vs TPC. Conclusions: T-DXd showed a statistically significant and clinically meaningful PFS benefit vs TPC (CT) in HER2-low mBC. HER2-ultralow results were consistent with HER2-low. Safety was in line with known profiles. DB-06 establishes T-DXd as a standard of care following ≥1 endocrine-based therapy for pts with HER2-low and -ultralow, HR+ mBC. Clinical trial information: NCT04494425 .[Table: see text]

Dose/Exposure Relationship of Exercise and Distant Recurrence in Primary Breast Cancer.

Postdiagnosis exercise is associated with lower breast cancer (BC) mortality but its link with risk of recurrence is less clear. We investigated the impact and dose-response relationship of exercise and recurrence in patients with primary BC. Multicenter prospective cohort analysis among 10,359 patients with primary BC from 26 centers in France between 2012 and 2018 enrolled in the CANcer TOxicities study, with follow-up through October 2021. Exercise exposure was assessed using the Global Physical Activity Questionnaire-16, quantified in standardized metabolic equivalent of task-hours per week (MET-h/wk). We examined the dose/exposure response of pretreatment exercise on distant recurrence-free interval (DRFI) for all patients and stratified by clinical subtype and menopausal status using inverse probability treatment weighted multivariable Cox models to estimate hazard ratios (HRs). For the overall cohort, the relationship between exercise and DRFI was nonlinear: increasing exercise ≥ 5 MET-h/wk was associated with an inverse linear reduction in DRFI events up to approximately 25 MET-h/wk; increasing exercise over this threshold did not provide any additional DRFI benefit. Compared with <5 MET-h/wk, the adjusted HR for DRFI was 0.82 (95% CI, 0.61 to 1.00) for ≥ 5 MET-h/wk. Stratification by subtype revealed the hormone receptor-/human epidermal growth factor receptor 2- (HR-/HER2-; HR, 0.59 [95% CI, 0.38 to 0.92]) and HR-/HER2+ (HR, 0.37 [95% CI, 0.14 to 0.96]) subtypes were preferentially responsive to exercise. The benefit of exercise was observed especially in the premenopausal population. Postdiagnosis/pretreatment exercise is associated with lower risk of DRFI events in a nonlinear fashion in primary BC; exercise has different impact on DRFI as a function of subtype and menopausal status.

Evaluation and treatment response in patients with hormone receptor-positive, HER2 low metastatic breast cancer: A single center retrospective analysis.

e13158 Background: Patients with Hormone Receptor (HR)+ metastatic breast cancer have seen several new options that improve overall survival. Recently, there are new treatment options for patients with HER2 low expression (defined as HER2 1+ on IHC or 2+ on IHC with a negative FISH). Currently, patients who have HR+ metastatic breast cancer are treated with a combination of an aromatase inhibitor and a Cyclin Dependent Kinase (CDK) 4/6 Inhibitor as first line. Information regarding response to therapy in this group and a correlation with HER2 expression is limited. Methods: This is a retrospective study that aimed to evaluate patients with metastatic, HR+, HER2 low or HER2 negative breast cancer between January 1, 2015 and December 31, 2022. Patients were stratified based on their HER2 status, race, presence of de-novo metastatic disease versus progression, treatment with a CDK 4/6 Inhibitor, and time to progression (defined as the date of biopsy-proved diagnosis to the date of radiographic progression). Comparative data analyses were performed using Fisher Exact and Kruskal-Wallis testing. Kaplan Meier estimates with a log rank p-value were used for survival curves, and a P-value of &lt; 0.05 was considered statistically significant. Results: 143 patients were included in our study. Patients were divided based on their HER2 status; 33.5% had HER2 2+ disease, 55.9% had HER2 1+, and 8.4% had HER2 0. Of the patients evaluated, 66% (94/143) were Caucasian, 25% (36/143) were African American (AA), and 9% (13/143) were of other race. There was a significant difference amongst patients treated with CDK 4/6 inhibitors when stratified by race; AA patients had a higher proportion of not using a CDK4 inhibitor (43.3% vs 20.3%; p-value 0.0109). There was a significant difference between the survival curves of HER2 0, 1+, and 2+ (log rank p-value = 0.043). HER2 0 patients progressed quicker than HER2 1+ and 2+ patients. When comparing HER2 negative and low disease, a significant difference was found between the survival curves (log rank p-value = 0.0190). In patients with HER2 low (1+ and 2+ with negative FISH) and HER2 negative disease, there was no difference noted among patients who had de-novo or progression to metastatic disease, high MiB1 status (defined as &gt;20%), whether treatment with CDK 4/6 inhibitor was used, and tumor histology. Conclusions: In our study, patients who had any HER2 expression had a longer time to progression compared to patients with no expression. Patients who had a higher expression (2+ vs 1+) displayed a longer time to progression. This may suggest that as the HER2 expression increases, they may derive a longer benefit with first line therapy. Interestingly, African American patients had a higher proportion of not using a CDK4/6 inhibitor. Larger studies are needed to evaluate these differences and determine whether any expression can be used as a prognostic marker.

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.

Mutational landscape of HER-2 low breast cancer.

e13040 Background: HER2-low breast cancer is defined as HER2 IHC score of 1+ or 2+/ISH- tumors. Anti-Her-2 therapies such as trastuzumab deruxtecan improve progression-free survival (PFS) and overall survival (OS) in patients with HER-2 low metastatic breast cancer. However, the mutational landscape of HER2-low BC is still not well defined. The aim of this study is to characterize the biological and clinicopathological landscape of HER2-low BC by next generation sequencing. Methods: We conducted a single institution, retrospective chart review of patients with metastatic breast cancer (MBC) from 1/2020 to 4/2023. We obtained Next generation sequencing data and correlated it with clinical outcomes. Patients with HER2 IHC score of 1+ or 2+/ISH- tumors referred as HER2-low, while with no HER2 IHC staining at all were referred as HER2-zero, and pts with HER2 IHC 3+ or HER2 IHC 2+/ISH+ referred as HER2+. Results: A total of 98 pts were enrolled:45 pts with HER2-low tumors, 29 pts with HER2+ and 24 pts with HER2-zero tumors. In the HER2-low cohort, 58% (26 pts) were initially diagnosed with loco regional disease while 42% presented with stage IV at diagnosis. On average patients were on 3 lines of therapy for metastatic disease (ranging between 1 to 12). Of those 35% received T-DXd. High Ki-67 proliferation (≥20), reported in 58% (26 pts). OS was 54.4 months, 95% CI [ 42.5,100.2]. In the HER2+ cohort, 31% of pts presented with stage IV at diagnosis. On average pts received 3 lines of therapy (ranging from 1 to 14). 69% of pts received T-DXd. High Ki-67 reported in 48% of pts. OS was 59.2 months, 95% CI [39.2,96,1]. In the HER2-zero, 62.5% of pts presented with stage IV. On average pts received 1 line of therapy (ranging between 1 to 5), 62% of pts had high Ki-67. OS of 41.6 months 95% CI [18.4, 77.9]. Conclusions: Although limited by the sample size, our data suggests that HER-2 low breast cancer tends to be more locally advanced or metastatic at the time of presentation. HER-2 low BC is associated with a higher Ki-67 index and tends to harbor more mutations. HER-2 low may not just be a target, but a unique biological entity and can be distinguished from HER2-Zero BC with higher prevalence of HR+ and other biomarkers and better OS. NGS data from a larger data set is required to better characterize HER-2 low breast cancer. We suggest that clinicians obtain NGS panel in all patients with HER-2 low MBC. [Table: see text]

Landscape of HER2-low breast cancer: Insights from a six-year study on incidence and clinicopathological characteristics.

e13148 Background: Human epidermal growth factor receptor 2 (HER2)-low breast cancer has emerged as a subtype of breast cancer, defined by HER2 1+ or 2+ in immunohistochemistry (IHC) and the absence of the ERBB2 gene amplification on fluorescence in situ hybridization (FISH). Recent trials showed marked response of HER2 breast cancer to novel anti-HER2 antibody-drug conjugates, rising interest in the HER2-low subtype. To date, data on characteristics of HER2-low breast cancer subtype is limited. Herein, we describe the clinicopathological characteristics of HER2-low breast cancer subtype compared HER2-zero/negative breast cancer. Methods: Real-world data from the Anatomic Pathology Division of Hotel Dieu de France, spanning 2017-2022, was retrospectively collected. Patients with HER2-IHC 3+ and HER2-IHC 2+ with ISH-amplified (HER2-positive) were excluded to compare HER2-low to HER2-zero breast cancer subtypes. Patients were then categorized based on their hormone receptor (HR) status. Clinicopathological characteristics between the groups were compared using a Chi-Square and Mann–Whitney U tests. Results: Out of 1195 patients, we observed 341 (28.5%) HER2-low breast cancers cases. HER2-positive breast cancer cases (n=178; 14.9%) were subsequently excluded. There was no significant difference in age and sex between the HER2-low and the HER2-zero group (p=0.3 and 0.8, respectively). HER2-low breast cancer was associated with positive estrogen receptor (ER) status and positive progesterone receptor (PR) status (p&lt;0.001 and p=0.01, respectively). Ductal adenocarcinomas were more frequently observed in the HER2-low group, whereas lobular and metaplastic adenocarcinomas were especially prevalent in the HER2-zero group (all p&lt;0.001). When stratified by HR status, 87.4% of patients had HR-positive status and 12.6% were HR-negative. Furthermore, the occurrence rate of tumors with a low Ki-67 labeling index was comparable between the two groups (p=0.9). However, among the HR-negative group, HER2-low tumors tended to show lower proliferation index compared to HER2-zero tumors (p = 0.04; Table). Conclusions: In conclusion, this study showed that HER2-low is a distinct from HER2-zero and is frequently present among patients with breast cancer. Clinicopathological features such as histological type differ between HER2-zero and HER2-low breast cancer. Our findings suggest that, within HR-negative breast cancer, breast cancer with low HER2 expression exhibits a less aggressive profile when compared to HER2-zero tumors. [Table: see text]

Comparative survival analysis of patients with HER2-low and HER2-positive metastatic breast cancer with or without brain metastases treated with trastuzumab deruxtecan.

1036 Background: Breast cancer outcomes vary among HER2-amplified and HER2 low-expression patients, particularly in the presence of brain metastases (BM). Trastuzumab deruxtecan (T-DXd) is FDA approved for the treatment of adult patients with unresectable or metastatic human epidermal growth factor receptor 2 (HER2)-low and HER2-positive (HER2+) patients (pts). This study aims to evaluate the impact of T-DXd treatment on overall survival among HER2 low and HER2-positive metastatic breast cancer (MBC) patients with and without brain metastases (BM). Methods: A retrospective analysis was conducted by using de-identified data available from seven US-based health systems part of Guardian Research Network (GRN). Patients treated with T-DXd from December 2019 to December 2023 with a diagnosis of HER2 low (immunohistochemistry [IHC] 1 + or IHC 2+/negative with HER2 FISH non-amplified) and HER2+ (IHC 3+ or HER2+ and FISH amplified MBC were included. Median overall survival (mOS), calculated from the initiation of T-DXd treatment, was assessed using Kaplan-Meier Curve analysis and Log-rank test. Results: A total of 380 MBC pts were identified. Among these 231 (61.1%) were stratified as having HER2 low and 149 (38.9%) HER2+ MBC. Pts with HER2+ disease had a higher prevalence of BM (n=70; 47%) compared to HER2-low pts (n=55;23.8%). The median age at BM diagnosis was 60.5 years, range: 21.6 to 87.1 years. Within the entire BM group (n=125), there were more pts with ER+ disease (81.9%) in the HER2 low group compared to HER2+ group (55.8%, p=0.01). The majority of these patients had multiple prior lines of therapy. HER2+ BM pts had a median overall survival (mOS) of 9.3 months [CI: 6.79-11.88, log rank p &lt;0.001], compared to 4.3 months [CI: 1.89-6.82, log rank p &lt;0.001] in the HER2-low pts. Without BM, HER2+ pts had a mOS of 10.7 months [CI: 0.71-20.82, log rank p &lt;0.001], compared to 6 months [CI: 3.47-8.67, log rank p &lt;0.001] in the HER2-low pts. Conclusions: In this retrospective study of heavily pretreated MBC patients with multiple prior lines of therapy, pts with HER2+ MBC with and without BM had a longer mOS compared to those with HER2- low disease, suggesting HER2 expression as a key determinant of T-DXd efficacy. Poor survival in MBC patients without BM was attributed to pre-treatment with multiple lines of therapy. Future research should explore combination therapies and predictive biomarkers while conducting clinical trials to optimize treatment strategies for HER2+ metastatic breast cancer patients.

Prognosis and tumor-infiltrating lymphocytes (TILs) in estrogen receptor (ER)-low metastatic breast cancer (MBC): Analysis from a large multi-institutional cohort and the TONIC phase II trial with nivolumab.

1100 Background: Although 1% as ER cutoff to discriminate ER+/HER2- from triple-negative (TN) BC serves the purpose of maximizing access to endocrine therapy, it may be suboptimally informative in terms of prognosis and immune checkpoint inhibitor (ICI) benefit. In the early setting, we reported that ER-low BC (ER 1-9%/HER2-) is immunologically and prognostically similar to TN (ER 0%) [Massa, 2023]. Here we focus on MBC and aim to assess prognosis of ER-low BC, including the conversion from ER+(≥10%)/HER2- to ER-low at relapse. We also compared ER-low and TN in terms of outcome after ICI, and TILs. Methods: We included two cohorts of MBC patients (pts): a multicentric retrospective cohort and pts with ER&lt;10%/HER2- MBC enrolled in the TONIC trial testing nivolumab +/- induction therapy. All pts had ER and HER2 status assessed on metastatic tumor lesion; in the retrospective cohort ER and HER2 status on primary tumor was also available. Survival endpoints in the retrospective cohort: overall survival (OS, from BC diagnosis), post-relapse survival (PRS, from BC relapse). Exploratory endpoints from the TONIC trial: clinical benefit rate (CBR), OS and PFS (both from randomization). TILs were assessed on MBC samples (both cohorts) and on matched primary tumor (retrospective cohort). Results: We included 1112 pts in the retrospective cohort: the prevalence of ER-low BC was 3.6% in primary tumor and 5.9% in MBC lesions. In the TONIC trial, 15/110 pts had ER-low MBC. In the retrospective cohort, ER-low and TN MBC showed similar outcome, and significantly unfavorable vs ER+/HER2- MBC (Table). Among pts with ER+/HER2- primary BC, 6.7% converted to ER-low and 14.7% to TN at relapse. ER+/HER2- BC pts converting to ER-low had similar outcome than those converted to TN, and significantly poorer than pts with stable ER+/HER2- (Table). In the TONIC trial, ER-low MBC pts, compared to TN, showed similar response to ICI (CBR: 20.0% vs 22.1%, p=1), similar PFS and numerically worse OS (Table). TIL levels on MBC samples were similar between ER-low and TN both in the retrospective (median: 6% vs 5%, p=0.83) and the TONIC cohorts (median: 5.5% vs 5.0%, p=0.56) and were higher than ER+/HER2- (median: 3%). Conclusions: We confirmed that ER-low and TN MBC show similar poor outcome and the shift from ER+/HER2- to ER-low has a comparable unfavorable prognostic impact compared to conversion to TN. Our results support the hypothesis that ER-low and TN are immunologically akin and similarly prone to respond to ICI. [Table: see text]

Can patients with biopsy-diagnosed DCIS safely spare sentinel lymph node biopsy (SLNB)?

e12583 Background: While the guidelines generally recommend that most patients with biopsy-diagnosed breast ductal carcinoma in situ (DCIS) can be spared from axillary staging if receiving breast conserving surgery, the percentage of such patients received SLNB is still as high as 50-70%. SOUND trial recently provides some low risk invasive breast cancer patients with the option of omitting SLNB, further highlighting the necessity of omitting SLNB in DCIS patients. This study aimed to retrospectively analyze the chance of turning into invasive cancer and lymph node metastasis in the patients who are diagnosed as DCIS by biopsy. Methods: Preoperative biopsy-diagnosed breast pure DCIS patients between 2011-2023 were retrospectively reviewed in Sun Yat-sen Memorial Hospital. Patients with axilla staging were grouped by pathology status (LN- versus LN+). Differences were compared using either t test or chi-squared test. Multi-variate logistic regression model was conducted to stratify the risk for LN metastasis. Results: 1193 patients were eligible for analysis, of whom 51.8% turned invasive breast cancer (IBC) in post-surgery pathology. 42% and 81% of IBCs were only T1mi and less than 1cm foci (T1a,b) respectively. 1161 (97.3%) patients had available axilla LN information and their axillary metastasis rate was 7.1% (0.9% and 12.5% in DCIS and IBC). Only 22 (1.9%) or 15 (1.3%) patients had ≥ 3 or 4 positive LN involved. Multi-variate analysis identified four risk factors associated with LN metastasis: ultrasound suspicious lymph node (OR=2.22, 95%CI: 1.21-4.07), tumor size (&gt;2cm vs ≤2cm: OR=2.85, 95%CI:1.10-7.42), biopsy method (core biopsy vs excision: OR=7.04, 95%CI:1.60-31.25) and necrosis (OR=2.20, 95%CI: 1.23-3.94). Among 440 patients with excision biopsy, only 1.4% had LN involved. In the other 721 patients diagnosed by core biopsy, the LN metastasis rate of patients who had 0,1,2 and 3 risk factors were 3.6%, 6%, 21% and 29.5%, respectively. Based on the number of risk factors patients were stratified to low risk (having 0-1 risk factor) and high risk (having ≥2 risk factors), with low risk patients having only 5.4% LN metastasis. Conclusions: Although the patients diagnosed with preoperative pure DCIS had a high chance of upgrading to invasive cancer, only 7.1% of them had lymph node metastasis. 98% of them are Z0011-eligible and 40% of them are SOUND-eligible if they receive breast conserving surgery, indicating the futility of axillary staging in these patients. We identified four independent risk factors for LN metastasis (suspicious lymph node on US, tumor size, biopsy method and necrosis). Even in the patients who received mastectomy, if they have only 0-1 risk factors, SLNB can still be safely omitted.

HER2 low hormone positive breast cancer: Unveiling the driver.

e12561 Background: A new HER2 targeting drug, Trastuzumab deruxtecan, has shown effectiveness among a subgroup of breast cancer (BC) patients previously reported as HER2 negative, challenging the established classification. HER2 low (IHC 1+ or IHC +2/ISH negative) require further study to understand their clinicopathological features and prognosis to determine whether they are indeed distinctly different from the HER2 negative subgroup. Methods: This retrospective study of 1029 early BC patients diagnosed between 2014 and 2022 in Alexandria university hospitals. Tumors originally reported as HER2 negative were reclassified into HER2 0 and HER2 low and stratified based on hormone receptor (HR) status. Clinical and pathological features were compared. Disease free survival (DFS), overall survival (OS) and time to recurrence (TTR) were calculated. Results: Out of the 1029 patients, 779 (75.7%) were reported as HER2 negative, after reviewing their files, 441 (56%) of them were found to be IHC 0, and 338 (43%) were HER2 low. 192 (18.7%) HER2 positive patients and 58 (5.6%) patients with undetermined HER2 status were excluded. HER2-low tumors were found to be positively associated with HR positive status compared to HER2-0 (302 [89.3%] vs. 368 [83.4%]; P=0.019). The rate of HER2-low significantly increased as the level of ER expression increased, from 37 of 190 (19.5%) ER-negative to 40 of 143 (28%) ER-low, 94 of 264(35.6%) ER-moderate and 167 of 432(38.7%) ER strong, p=&lt;0.001. ER2-low were more likely to be ductal carcinoma (88.1% vs. 80.4%; p=0.004), and to have Ki67 level &lt;20 (55% vs. 33%; p=0.008). When stratified according to HR status, ductal histology was still significantly higher in the HER2 low HR positive subgroup compared to the HER2-0 HR positive (87.6% vs. 80.3%; p=0.011). No significant difference between HER2-0 and HER2-low regarding age at presentation, menopausal status, tumor size, lymph node status, lymphovascular invasion, high grade, multifocality or extensive intraductal component. Median follow-up duration was 55 months, no significant differences between HER2-0 and HER2 low groups regarding relapse rate (22.6% vs. 21.6%), 5-year DFS (76.4% vs. 78%) or 5-year OS (81.7% vs. 87.4%), however TTR was significantly longer in the HER2 low HR positive group compared to the HER2-0 HR positive group (41.6 months vs. 31.3 months; p= 0.031). Conclusions: A positive correlation was observed between HER2 low and estrogen receptor positivity, as well as its level of expression. No significant differences were found between HER2 low and HER2-0 to support classifying HER2 low as a distinct group.

Real world outcomes of sequential ADC therapy in metastatic breast cancer: Patients treated with sacituzumab govitecan and trastuzumab deruxtecan.

1085 Background: Sacituzumab govitecan (SG) and trastuzumab deruxtecan (TDXd) are antibody drug conjugates (ADCs) that are approved for the treatment of HER2 low metastatic breast cancer (MBC). Both carry payloads which inhibit topoisomerase 1, and it is unknown whether these ADCs retain clinical activity when used sequentially to each other. Here we present a retrospective study of patients treated with both SG and TDXd at our institution and report real world progression free survival (PFS), clinical factors associated with longer PFS, and whether ADC sequence impacts outcome. Methods: All patients with MBC treated at MSKCC who had received both SG and TDXd (in any order) were eligible for inclusion. Clinicopathological and demographic data were obtained from retrospective chart review. PFS was determined clinically and calculated using Kaplan-Meier survival analysis. Univariate and multivariate associations of survival were assessed using Cox proportional hazards models. Results: Eighty-five patients met eligibility per the criteria above: 54 with estrogen receptor positive (ER+) MBC and 31 with triple negative breast cancer (TNBC). 33 patients received SG followed by TDXd (14 ER+, 19 TNBC), and 52 received TDXd followed by SG (40 ER+, 12 TNBC). Median age at time of second ADC treatment (ADC2) was 59 among all patients, 62 among SG first, and 58 among TDXd first. This cohort was heavily pre-treated, with median 5 prior therapies at the time of first ADC (ADC1) and 7 at the time of ADC2. Both the SG first and TDXd first cohorts had median 1 line of intervening therapy between ADCs. In the SG first group, median ADC2 (TDXd) PFS was 3.5 months (95%CI 2.7-7.7), and in the TDXd first group median ADC2 (SG) was 2.8 months (95%CI 2.6-3.7). On multivariate analysis, neither ADC sequence (SG first vs. TDXd first, HR 1.30, 95%CI 0.71-2.37, p=0.4) nor ER status (TNBC vs. ER+, HR 1.21, 95%CI 0.63-2.32, p=0.6) showed statistically significant differences in ADC2 PFS between these groups. Instead, later treatment line at the time of ADC2 was significantly associated with shorter ADC2 PFS (continuous, HR 1.11, 95%CI 1.01-1.23, p=0.03). To separately evaluate differences in PFS for each ADC depending upon whether it was first or follow-up therapy, median ADC1 vs. ADC2 PFS is summarized by ADC (Table). Conclusions: In this heavily pre-treated patient cohort, the clinical activity of both SG and TDXd appear modest in the ADC2 setting. Further studies are needed to confirm these findings and to determine whether payload cross-resistance may undermine the benefit of sequential ADC therapy. [Table: see text]

Clinicopathological characteristics and outcomes of patients with HER2-low breast cancer: 6-year ambispective cohort study from India.

e23260 Background: Patients with low HER2-positive breast cancers are treated like those who are entirely HER2-negative. The DESTINY-Breast trials have proven Trastuzumab deruxtecan's benefit in the low HER2 subset. In Literature, limited data is available regarding the characteristics and outcomes of patients with low HER2 positivity from India. This study is done to address this research gap. Methods: This was an ambispective cohort study where we analysed the patients with carcinoma breast who were treated at our institute in the last 6 years. Out of 1845 patients, 243 were identified to have low HER2 expression. Patients were classified as Low HER2 positive if they had HER2 1+ or 2+ by IHC and negative by FISH. The clinical and pathological characteristics, progression-free survival (PFS) and overall survival (OS) of HER2 low subset, Estrogen Receptor (ER) positive and negative HER2 low cohorts and Metastatic (MBC) HER2 low patients were analysed separately. Results: A total of 243 patients were analysed. Of which 157 had HER2 2+ and 86 had 1+ expression. 240 were females. 79.8% were ER+ and 20.2% were ER negative among the total patients. 76.7% and 81.5% were ER+ in HER2 1+ and 2+ cohorts respectively. 78.2% were non-metastatic and 21.8% had MBC. 34.6% were treated with Neoadjuvant chemotherapy (NACT) and 42.4% with adjuvant chemotherapy (CT). 4.5% of patients treated with NACT attained PCR. 53.1% had T2, 16.8% had T4 disease. Most of the patients had N0 (35.4%) and N1(37%) disease. The OS of all low HER2+ patients were 4.97 years 95%CI(4.72-5.22). The OS in HER1+ and 2+ cohorts were 4.08 years and 5.04 years respectively. The PFS in low HER2+ patients was 5.01 years 95%CI(4.74-5.27) and 4.29 years and 4.89 years in HER2 1+ and 2+ cohorts. In the ER+ and negative cohorts, 31.4% of ER+ were treated with NACT and 45.4% of ER+ patients were treated with adjuvant CT. Most of ER+ low HER2 patients were of T2 stage (53.6%, p = 0.037). 36.6% were N0 and 34% were N1. 14.4% of ER+ low HER2 were MBC and 16.3% ER negative low HER2 were MBC. The OS of ER+ lowHER2+ cohort was 4.44 years and ER- HER2+ cohort was 4.43 years. Patients with MBC had a larger tumour size and nodal positivity (T4 43.4%, N1 37.8%,p = 0.001). The PFS and OS in MBC were 3.42 and 3.07 years compared to 5.29 years and 5.37 years in non-metastatic patients. Patients who were treated with NACT had an OS and PFS of 4.24 and 4.20 years and those who were treated with adjuvant CT had an OS of 5.39 years. Conclusions: The data on low HER2-positive patients is scarce in the Indian population. The low HER2+ patients had a PFS of 4.97 years and an OS of 5.01 years. Most of the patients had a T2 and N1 disease. The research gap low HER2+ subset is significant, especially considering the recent approval of trastuzumab deruxtican in India. With ongoing trials in MBC and non-metastatic settings, the benefit from this newer option may become clearer, particularly in ER+ low HER2 subset.

A meta-analysis of the difference in response to trastuzumab-deruxtecan (T-DXd) based on HER2 immunohistochemistry (IHC) in HER2 low metastatic breast cancer (mBC).

e13164 Background: HER2 low BC have an IHC staining of 1+ or 2+ with negative fluorescence in situ hybridization (ISH). Although T-DXd is approved for this, difference in activity between 1+ and 2+ is uncertain. Methods: A systematic search with controlled vocabulary encompassing BC and T-DXd was conducted in PubMed, Embase, Scopus, and Cochrane on November 11 2023 with no search restrictions. 2318 records were identified and duplicates were removed using Mendeley. The remaining 1189 records were imported into Rayyan, and the titles were screened independently by 2 reviewers. 47/75 full texts were relevant, of which 4 [3 clinical trials, 1 retrospective study] were included for analysis. Only studies that provided outcome data for HER2 1+ and 2+ ISH- were included. RevMan was used to analyze the Risk Ratio (RR) and Odds Ratio (OR) with 95% Confidence Interval (CI), derived from Random Effects (RE) model with Mantel-Haenszel (MH) method. Pooled proportions (PP) were determined using OpenMeta. Results: There were a total of 264 patients in 1+ and 204 in 2+ISH-. Median age was 57 years. All studies had pre-treated mBC. T-DXd dose was at least 5.4 mg/kg every 3 weeks. Visual inspection of our funnel plots revealed no bias. PP (3/4 studies) for patients achieving an Objective Response Rate (ORR) [Complete Response (CR)+Partial Response (PR)] was 42.9% (31.6-54.2%) in 1+ and 38% (26.3-49.7%) in 2+. The median Progression free survival (2/4 studies) was 8.6 (1+) and 7.95 (2+) months respectively. RE RR (3/4 studies) for Progressive Disease (PD) showed no difference between 1+ and 2+ [0.93 (0.80, 1.10), p=0.4, I²=0%]. Similarly, RE OR (3/4 studies) for Disease Control Rate (DCR) [CR+PR+Stable disease (SD)] [1.20 (0.78, 1.85), p=0.41, I²=0%], ORR [1.17 (0.58, 2.34), p=0.66, I²=0%], and PR [1.05 (0.52, 2.11), p=0.89, I²=0%] showed no significant difference between 1+ and 2+ (Table). Conclusions: Our results indicate no difference in response to T-DXd between 1+ and 2+, solidifying its role as a treatment option in HER2 low mBC. Limited number and heterogeneity between studies are limitations of our study, which ought to be addressed in future trials through clear subgroup stratification between 1+ and 2+. [Table: see text]

Differential genomic profiling of the progesterone receptor (PR) negative and estrogen receptor (ER) low metastatic breast cancer subtypes through circulating tumor DNA: A TNBC-like disease subtype?

1039 Background: ER positive/HER2 negative metastatic breast cancer (MBC) is typically regarded as a single entity, although significant clinical differences are often observed, especially in the ER low subgroup (ER&lt;10% regardless of PR status). This study aims to investigate genomic differences among HER2 negative subtypes (i.e., ERlow, PRpos [ER &gt;10%/PRpositve], PRneg [ER &gt;10%/PRnegative], triple negative [TNBC]) through circulating tumor DNA (ctDNA) next-generation sequencing (NGS). Methods: The study analyzed a retrospective cohort of 879 patients (pts) with HER2 negative MBC with ctDNA testing using the Guardant360 NGS panel within a large multicenter academic consortium. ER, PR and HER2 status was defined based on the most updated biopsy. Associations across single nucleotide and copy number variations (SNVs and CNVs) and ER/PR status were tested by multinomial logistic regression in terms of Relative Risk Ratio (RRR), adjusting for significant clinical characteristics (i.e., lines of treatment, metastatic sites, histology). Oncogenic pathway was defined based on reference (1). Prognosis was analyzed through Cox regression for overall survival (OS) defined from time of ctDNA collection. Results: Among the 879 analyzed pts, PRpos was the most prevalent subtype (N:420, 48%), followed by PRneg (N:216, 24%), TNBC (N:209, 24%), and ERlow (N:34, 4%). Compared to PRpos, lobular MBC was less common in TNBC (RRR: 0.33, P=0.001), while lung involvement was more frequent in TNBC (RRR: 1.53, P=0.019), and liver involvement in PRneg (RRR: 1.44, P=0.035). In contrast, bone metastases were less common in TNBC and ERlow (RRR: 0.26, P&lt;0.001 and RRR: 0.45, P=0.03, respectively). After multivariable analysis, ERlow and TNBC were associated with a higher incidence of TP53 SNVs (RRR: 5.42, P&lt;0.001 and RRR: 3.08, P=0.007, respectively) and a lower incidence of ESR1 SNVs (RRR: 0.23, P=0.025 and not detected, respectively). TNBC exhibited significantly fewer PIK3CA SNVs (RRR: 0.41, P=0.005) and CCND1 CNVs (RRR: 0.20, P=0.009), along with a higher frequency of CCNE1 CNVs (RRR: 6.47, P&lt;0.001). PRneg had a lower incidence of ESR1 SNVs (RRR: 0.52, P=0.013) and more frequent FGFR1 CNVs (RRR: 2.61, P=0.004). Similar results were observed across oncogenic pathways. Compared to PRpos, OS analysis indicated poorer outcomes across all subgroups (PRneg HR: 1.29 P = 0.035, TNBC HR: 1.96 P&lt;0.001, ERlow HR: 2.32 P&lt;0.001). Conclusions: This study highlights several clinical and molecular similarities between TNBC and ERlow MBC, while suggesting specific endocrine resistance mechanisms in PRneg that are less reliant on ESR1 and more exposed to alternative mechanisms such as FGFR1 amplification. These findings underscore the importance of more precise disease subtyping to inform future drug development trials. 1. Sanchez-Vega F et al, Cell. 2018.