Negative Breast Cancer Research Articles

Development of a nomogram to predict recurrence scores obtained using Oncotype DX in Japanese patients with breast cancer

BackgroundChemotherapy is crucial for hormone receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer, and its survival benefits may outweigh adverse events. Oncotype DX (ODX) assesses this balance; however, it is expensive. Using nomograms to identify cases requiring ODX may be economically beneficial. We aimed to identify clinicopathological variables that correlated with the recurrence score (RS) and develop a nomogram that predicted the RS.MethodsWe included 457 patients with estrogen receptor-positive, HER2-negative breast cancer with metastases in fewer than four axillary lymph nodes who underwent surgery and ODX at our hospital between 2007 and 2023. We developed nomograms and internally validated them in 310 patients who underwent surgery between 2007 and 2021 and validated the model’s performance in 147 patients who underwent surgery between 2022 and 2023.ResultsLogistic regression analysis revealed that progesterone receptor (PgR) level, histological grade (HG), and Ki67 index independently predicted the RS. A nomogram was developed using these variables to predict the RS (area under the curve [AUC], 0.870; 95% confidence interval [CI], 0.82–0.92). The nomogram was applied to the model validation group (AUC, 0.877; 95% CI, 0.80–0.95). When the sensitivity of the nomogram was 90%, the model was able to identify 52.3% low-RS and 41.2% high-RS cases not requiring ODX.ConclusionsThis was the first nomogram model developed based on data from a cohort of Japanese women. It may help determine the indications for ODX and the use of nomogram to identify cases requiring ODX may be economically beneficial.

Attempt to Substitute the Oncotype DX Breast Recurrence Score® Test by Histopathological Factors and MUC1 Protein Expression.

Oncotype DX Breast Recurrence Score® test (ODx) is a gene profiling assay predicting the benefit of adjuvant chemotherapy for early-stage hormone receptor (HR)-positive and human epidermal growth factor receptor 2 (HER2)-negative breast cancer. Meanwhile, to avoid unnecessary financial burden on the patient, many studies have attempted to establish alternatives to ODx using conventional clinicopathological factors, but these have not yet been successful. Thus, we retrospectively investigated clinicopathological factors to establish alternatives to ODx. Data from 114 Japanese women who underwent ODx were retrospectively examined to investigate the relationship between ODx recurrence score (RS) and clinicopathological features, including MUC1 staining patterns on immunohistochemical assessment. An RS of 0-25 was defined as low, and 26-100 as high. Ninety patients (79%) had low RS and 24 patients (21%) had high RS. Univariate analysis revealed that low tumor grade, high progesterone receptor (PgR) expression, and low Ki67 labeling index (LI) were significantly associated with low RS (p=0.025, p<0.001, and p<0.001, respectively). Tumors with an apical pattern of MUC1 staining also frequently had a low RS (p=0.024). In multivariate analysis, PgR expression and Ki67 LI were independent factors associated with RS (p<0.001, for both). When the ODx results were categorized with a combination of these two factors, only 2% of the PgR-high and Ki67-low group (one in 51 cases) had a high RS. PgR expression and Ki67 LI were independent factors correlated with RS. MUC1 staining pattern also has the potential to be a useful marker. We believe that it is crucial to continue attempts to identify patients who are unlikely to benefit from ODx.

Breast cancer epigenetics: current and evolving treatment.

Breast cancer (BC) presents persistent challenges due to subtype-specific limited efficacy and potential resistance to standard therapy, influenced by the dynamic reversible nature of epigenetic plasticity. This study aims to comprehensively explore the evolving BC epigenetic landscape, analyzing trends and evaluating the therapeutic potential of epigenetic drugs (epi-drugs) for BC treatment. We conducted a cross-sectional study of BC epigenetic trials using ClinicalTrials.gov until July 18, 2023. Additionally, results from randomized controlled trials were retrieved from the registry or PubMed using trial registration numbers. In total, 22 epi-drugs were investigated in 100 trials, with 11 currently being studied in 38 ongoing trials for BC. Over the years, epigenetic clinical trials for BC have notably increased, with histone deacetylase inhibitors constituting 45.45% of the candidate agents in the development pipeline. All ongoing trials are enrolling human epidermal growth factor receptor2 (HER2)-negative BC patients. Epi-drugs are commonly explored in combination with multiple anti-cancer therapies, such as aromatase or microtubule inhibitors, using an intermittent sequential administration approach. Emerging strategies include new-generation epi-drugs and combination involving immunotherapy or targeted therapy. Among candidate drugs, tucidinostat and entinostat, in combination with exemestane, demonstrated significant improvements in progression-free survival in phase III trials for hormone receptor-positive, HER2-negative BC patients. This study highlights the growing interest in BC epigenetics, suggesting a potential shift from a one-size-fits-all approach to precision medicine, and emphasizes the necessity for robust evidence on their efficacy and safety to support continuous development and approval, addressing the unmet needs in BC treatment.

New evidence: Metformin unsuitable as routine adjuvant for breast cancer: a drug-target mendelian randomization analysis

PurposeThe potential efficacy of metformin in breast cancer (BC) has been hotly discussed but never conclusive. This genetics-based study aimed to evaluate the relationships between metformin targets and BC risk.MethodsMetformin targets from DrugBank and genome-wide association study (GWAS) data from IEU OpenGWAS and FinnGen were used to investigate the breast cancer (BC)-metformin causal link with various Mendelian Randomization (MR) methods (e.g., inverse-variance-weighting). The genetic association between type 2 diabetes (T2D) and the drug target of metformin was also analyzed as a positive control. Sensitivity and pleiotropic tests ensured reliability.ResultsThe primary targets of metformin are PRKAB1, ETFDH and GPD1L. We found a causal association between PRKAB1 and T2D (odds ratio [OR] 0.959, P = 0.002), but no causal relationship was observed between metformin targets and overall BC risk (PRKAB1: OR 0.990, P = 0.530; ETFDH: OR 0.986, P = 0.592; GPD1L: OR 1.002, P = 0.806). A noteworthy causal relationship was observed between ETFDH and estrogen receptor (ER)-positive BC (OR 0.867, P = 0.018), and between GPD1L and human epidermal growth factor receptor 2 (HER2)-negative BC (OR 0.966, P = 0.040). Other group analyses did not yield positive results.ConclusionThe star target of metformin, PRKAB1, does not exhibit a substantial causal association with the risk of BC. Conversely, metformin, acting as an inhibitor of ETFDH and GPD1L, may potentially elevate the likelihood of developing ER-positive BC and HER2-negative BC. Consequently, it is not advisable to employ metformin as a standard supplementary therapy for BC patients without T2D.

Cisplatin Monotherapy as a Treatment Option for Patients with HER-2 Negative Breast Cancer Experiencing Hepatic Visceral Crisis or Impending Visceral Crisis.

Hepatic visceral crisis (VC), characterized by a rapid total bilirubin increase with disease progression, poses a life-threatening risk in advanced breast cancer (ABC). International consensus guidelines define VC and touch on impending VC (IVC). Limited data exist on systemic treatments for hepatic VC/IVC. This study explores the safety and efficacy of cisplatin monotherapy in patients with Human Epidermal Growth Factor Receptor 2- negative breast cancer (BC) and hepatic IVC/VC. In this retrospective single-center cohort study data of patients treated with cisplatin monotherapy (60-80mg/m2, every 3-4weeks) between 2016 and 2023 at a reference Cancer Centre in Southern Poland were analyzed. 33 female patients (24/33 hormonal-positive) with the mean age 53.84years were included. Participants progressed on median 2 prior palliative systemic treatment lines. In 10/23 patients hepatic VC and in 23/33 IVC (rapid, symptomatic liver progression; extensive liver involvement; alanine or aspartate aminotransferase > 2 × normal limit; significant increases in lactate dehydrogenase, alkaline phosphatase, or gamma-glutamyl transferase) were identified. Median progression-free survival was 1.87months and median overall survival 2.67months. 33% of the patients presented stable disease or partial response. Eight patients experienced adverse events grade ≥ 3: in five the dose of cisplatin was reduced; two stopped the treatment. Due to the hepatotoxicity of BC-active drugs, specific recommendations for systemic treatment are scarce. Our study explored cisplatin's potential use, finding it to be a viable option in patients with performance status 0 or 1 experiencing hepatic IVC/VC, irrespective of liver function parameters and other factors.

Results of a retrospective study on the efficacy and safety of alpelisib in patients with HR+/HER2- metastatic breast cancer in real-world clinical practice.

e13058 Background: The combination of alpelisib and fulvestrant is an optimal therapy option for patients with hormone receptor-positive (HR+), HER2-negative (HER2–) metastatic breast cancer with PIK3CA gene mutations. The aim of this work to retrospectively analyze the efficacy and safety of alpelisib in real-world clinical practice in patients with pre-treated luminal HER2– negative metastatic breast cancer. Methods: The study included an analysis of 33 patients with widespread luminal HER2- negative breast cancer with detected PIK3CA gene mutation. The median age was 57 ± 13 months (95% CI 52-62). In 12 (36.4%) patients, the PIK3CA gene mutation was detected in exon 9, and in 21 (63.6%) – in exon 20. Alpelisib was prescribed to pre-treated patients in different lines. Most women (32/33; 97%) had received ET combined regimens with CDK4/6 inhibitors before starting alpelisib therapy: 14 (42.4%) patients underwent palbociclib therapy in combination with fulvestrant; 4 (12.1%) – palbociclib with aromatase inhibitors; 13 (39.5%) – ribociclib in combination with fulvestrant; 1 (3.0%) – ribociclib with aromatase inhibitors. It is important to note that 63.6% of patients had previous progression on fulvestrant monotherapy and 72.7% on aromatase inhibitor therapy. Patients with luminal B-subtype of breast cancer dominated - 72.7% (24/33). Results: The median overall survival (OS) in this study was 14 ± 2.5 months (95% CI: 9-18.9), and the median progression-free survival (PFS) was 6 ± 2.7 months (95% CI: 0.7-11.3). The rate of objective response was 30.3%, and prolonged disease stabilization was observed in 24.2% of cases. Prognostic factors were brain metastases (increasing the risk of death by 18 times) and discontinuation of the drug for any reason (increasing the risk of death by 8 times). It should be noted that the main reason for discontinuation or disruption of the drug's timing was unmanageable toxicity. All patients registered adverse events of varying degrees, with 21 (63.6%) patients experiencing hyperglycemia (grade 3-4 – 30.3%) and 14 (42.4%) patients experiencing skin toxicity (grade 3-4 – 15.2%). In the SOLAR-1 study, the frequency of hyperglycemia was comparable (64.8%), and rash was noted in a third of all patients, which is comparable to our data. Conclusions: The results of using alpelisib with fulvestrant confirm its effectiveness in real-world clinical practice in patients with pre-treated HR+HER2- negative widespread breast cancer with the presence of somatic PIK3CA gene mutation. Brain involvement is an unfavorable prognostic factor in patients with PIK3CA mutation and increases the risk of death by 18 times, requiring the need to optimize the therapeutic algorithm, including through radiation methods. Discontinuation of the drug, which increases the risk of death by 8 times.

Unveiling the relationship between the UGT2B gene family and neoadjuvant treatment response in patients with HER2-positive breast cancer.

e12651 Background: Achieving a pathological complete response (pCR) following neoadjuvant treatment (NAT) in HER2-positive tumors significantly enhances patient survival, resulting in a remarkable 92% reduction in mortality risk. However, it is crucial to identify biomarkers capable of predicting the NAT response, moving towards more personalized medicine. This approach would enable the identification of patients likely to respond to specific therapies, thereby facilitating the implementation of targeted treatment strategies. Our study aims to identify potential molecular biomarkers predictive of NAT response through a comprehensive analysis of differential gene expression in tissue samples from patients with HER2-positive, hormone receptor (HR)-negative breast cancer. Methods: Total RNA was extracted from FFPE tissue samples from two independent cohorts of women diagnosed with localized or locally advanced HER2-positive, HR-negative breast cancer. These patients underwent NAT in several hospitals in Andalusia, Spain. Standard chemotherapy, including taxanes and/or anthracyclines, and targeted anti-HER2 treatment such as trastuzumab and pertuzumab were administered. The patients were stratified into responders (R), achieving pCR, and non-responders (nR). In a discovery cohort (n=20), RNA hybridization using Clariom D microarray was conducted to discern differentially expressed transcripts between R and nR. Subsequently, gene expression patterns, and related pathways involved in NAT response, were analyzed using Transcriptome Analysis Console (TAC). The selected transcripts then underwent validation through quantitative PCR (qPCR) in an independent cohort (n=40). The area under the receiver operating characteristic (ROC) curve was used to evaluate the sensitivity and specificity of the genes as predictive biomarkers. Results: Microarray analysis of the discovery cohort, revealed 954 differentially expressed transcripts between R and nR, following criteria of fold change greater than 1.5 or less than -1.5 and a p-value below 0.05. Among these, 643 were upregulated, while 311 were downregulated in nR compared to R. Bioinformatic analysis and a comprehensive literature review guided the selection of genes UGT2B10, UGT2B11, UGT2B15, UGT2B17, and UGT2B28 for further investigation. Subsequent qPCR analysis in the validation cohort, demonstrated the overexpression of these genes in non-responders, with statistical significance achieved only for UGT2B15. Conclusions: The UGT2B family genes encode enzymes involved in glucuronidation and metabolic pathways associated with drug detoxification and elimination. Our findings suggest that variations in the UGT2B15 expression may impact the metabolism rate of specific drugs, underscoring the necessity for additional research in this area.

ETHAN: A phase II study comparing different endocrine therapies for male breast cancer.

TPS632 Background: Male breast cancer is a rare disease, and most cases are hormone receptor-positive (HR+). Due to a lack of clinical trials, male breast cancer has historically been treated based on data extrapolated from women. However, there are substantial knowledge gaps in the comparative efficacy, safety, and patient-reported outcomes of endocrine therapies for male breast cancer. While tamoxifen is the current standard of care, additional data are warranted for aromatase inhibitors (AI), gonadal suppression, and cyclin-dependent kinase 4/6 (CDK4/6) inhibitors. Methods: This is an open-label, multicenter, randomized, phase II trial designed to evaluate different endocrine therapies in men with HR+ and human epidermal growth factor receptor 2 (HER2)-negative breast cancer. A total of 60 men will be enrolled across nine (9) sites within the Translational Breast Cancer Research Consortium (TBCRC). Key eligibility criteria include male sex and stage I, II, or III HR+/HER2- breast cancer before surgical resection of the primary tumor and axillary nodes. Key exclusion criteria include prior anti-cancer therapy for the current breast cancer or any other malignancy within the past 12 months, and inflammatory breast cancer. The trial has two phases. The first phase is a window of opportunity component in which newly diagnosed men are randomized 1:1:1 to either tamoxifen (Arm A), anastrozole (Arm B), or anastrozole plus degarelix (Arm C) given for three weeks. The primary endpoint for the window phase is Ki-67 reduction from the baseline diagnostic biopsy to the research biopsy at the end of the window phase. The second phase consists of neoadjuvant treatment, in which the tamoxifen group is randomized 1:1 to tamoxifen (Arm D) versus tamoxifen plus abemaciclib (Arm E), and the anastrozole alone (Arm B) and anastrozole plus degarelix (Arm C) groups are merged and then randomized 1:1 to anastrozole plus degarelix (Arm F) versus anastrozole plus degarelix plus abemaciclib (Arm G). The duration of the neoadjuvant phase is four (4) months, and the primary endpoint of this phase is residual cancer burden (RCB) index at time of surgery. The trial is powered for the RCB endpoint in a 2 x 2 factorial design to detect a 0.6 unit decrease in RCB index with 80% power and alpha=10%. For the Ki-67 endpoint, we assume an approximately 50% reduction in Arms A and B; Arm C will be of interest if it leads to ≥80% reduction in Ki-67. Secondary endpoints include: estradiol and testosterone levels at baseline, end of window, and during neoadjuvant phase; preoperative endocrine prognostic index (PEPI) score at surgery; adverse events; and patient-reported outcomes (including quality of life). Tumor tissue will be collected for correlative analyses. The study opened to enrollment at Dana-Farber in October 2023, and additional sites will open in 2024. Clinical trial information: NCT05501704 .

Clinical relevance of clinical treatment score post 5 years (CTS5) in HR-positive, HER2-positive breast cancer: An exploratory analysis from the HERA trial.

519 Background: The clinical treatment score post-5 years (CTS5) has proven valuable in assessing the necessity for extended endocrine therapy among patients with early-stage hormone-receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer. This study aimed to explore the potential of CTS5 as a predictive tool for long-term survival beyond five years in patients with specifically HR-positive, HER2-positive breast cancer. Methods: We collected patient-level data from the HERceptin Adjuvant (HERA) (BIG1-01; NCT00045032) trial. Our investigation focused on assessing the risk of late distant recurrence (DR) and overall survival (OS) according to the CTS5 risk score as continuous value and CTS5 stratification risk groups. Furthermore, we performed a Cox-regression analysis to determine the prognostic performance of CTS5, stratifying subgroups by age and administration of trastuzumab. Results: A total of 1,818 patients with HR-positive, HER2-positive breast cancer were included in this analysis. The CTS5 score, as a continuous variable, emerged as an independent prognostic factor for both late DR (adjusted HR, 2.04; 95% CI, 1.62-2.57; P &lt; 0.001) and OS (adjusted HR, 2.02; 95% CI, 1.58-2.58; P &lt; 0.001), respectively. In addition, multivariable analysis showed a significant association between the high-risk group and adverse outcomes in late DR (adjusted HR, 2.76; 95% CI, 1.84-4.15; P &lt; 0.001) and OS (adjusted HR, 2.45; 95% CI, 1.60-3.74; P &lt; 0.001) compared to low/intermediate group. Consistent results were observed, regardless of age or administration of HER2-targeted therapy. Conclusions: CTS5 is a useful prognostic tool for predicting late DR and OS in HR-positive, HER2-positive breast cancer patients. Extension of endocrine therapy should be actively considered in patients with CTS5 high-risk group.

Electronic clinical quality measure (eCQM) concordance and quality care disparities among patients with breast cancer (BC).

e23237 Background: BC mortality is decreasing steadily, yet disparities in treatment and outcomes persist. eCQMs are metrics specified in a standard electronic format using data from electronic health records (EHR) and other systems to measure care quality. CancerLinQ is a health technology platform aggregating EHR data from ~7M patients (pts) seen in US oncology practices and cancer centers. This analysis assesses odds of non-concordance with 4 BC-specific eCQMs in CancerLinQ. Methods: Pts actively treated for BC in 2021 in CancerLinQ data were included in this study. The following four practice-level eCQMs were assessed as proportions of BC pts who: eCQM1 – Undergo HER2 testing eCQM2 – Are &lt; age 70 with early-stage, hormone receptor (HR) negative BC who receive combination chemotherapy &lt; 4 months of dx eCQM3 – Have early-stage, HER2+ BC and receive trastuzumab eCQM4 – Have early-stage, HR+ BC and receive tamoxifen or an aromatase inhibitor (AI) &lt; 1-year of dx Ethnicity, race, age at dx, pt/practice rural status, and practice type were assessed as covariates. Adjusted odds ratios (aOR) and 95% confidence intervals (95% CI) were calculated for associations among study variables and receipt of guideline non-concordant care. Results: aORs (95% CI) of pt characteristics were compared to reference groups - non-Hispanic, white, age at dx 60-69, married, urban: eCQM1 (N = 21296): For unknown ethnicity, aOR (95% CI) = 1.5 (1.3 1.6); unknown race = 1.3 (1.2, 1.5); age 70-79 = 1.1 (1.0, 1.2), age 80-89 = 1.4 (1.2, 1.5), age &gt; 90 = 1.5 (1.1, 2.2); formerly married/partnered = 1.2 (1.1, 1.3), thus having greater odds of non-concordance. Age 40-49, aOR (95% CI) = 0.9 (0.8, 0.986), had lower odds of non-concordance. eCQM2 (N = 1259): For unknown ethnicity, aOR (95% CI) = 1.9 (1.2, 3.1); Asian = 2.9 (1.7, 4.9) or other race = 2.3 (1.2, 4.1); and formerly married/partnered = 1.7 (1.2, 2.6), thus having greater odds of non-concordance. Pts age &lt; 40 = 0.6 (0.3, 0.9) had lower odds of non-concordance. eCQM3 (N = 1341): Age &gt; 80, aOR (95% CI) = 3.8 (1.5, 9.1), had greater odds of non-concordance. eCQM4 (N = 5063): For age &lt; 40, aOR (95% CI) = 2.9 (2.1, 4.1), age 40-49 = 1.6 (1.2, 2.0), and age 50-59 = 1.5 (1.2, 1.9); and formerly married/partnered = 1.3 (1.1, 1.7), thus having greater odds of non-concordance. Conclusions: As expected, pts &lt; 40 had greater odds of receiving chemotherapy and pts &gt; 80 had lower odds of receiving trastuzumab, possibly due to cardiotoxicity concerns. Although all women with early-stage HR+ BC are potential tamoxifen/AI candidates, pts &lt; 60 with early-stage HR+ BC had greater odds of not receiving tamoxifen/AI compared to those age 60-69. Additionally, divorced, separated, or widowed pts had greater odds of non-concordant care in 3 of 4 of eCQMs assessed. Our findings demonstrate the ability of eCQMs to identify clinical subgroups more likely to receive non-concordant care who may be eligible for targeted interventions.

Association of circulating T lymphocytes and their functional states with pathologic complete response (pCR) in breast cancer (BC). A prospective Italian study.

559 Background: In BC, pCR is associated with substantial survival benefit. Hence, escalated neoadjuvant treatments (NATs) are being increasingly employed to improve pCR rates, warranting biomarkers for better patients’ selection. T-cell exhaustion and senescence are dysfunctional states that coexist in patients with cancer, impairing antitumor immunity and sustaining a suppressive immune microenvironment. Here, we assessed the impact of such states on pCR across different BC subtypes and NATs. Methods: This is a prospective study on patients undergoing NAT for BC at the Maggiore Hospital of Novara, Italy. Blood was collected at baseline and after NAT. Circulating T lymphocytes were characterized with exhausted (CD28, PD1, LAG3) and senescent (CD57, KLRG-1) biomarkers utilizing flow cytometry. Neutrophiles/lymphocytes ratio (NLR) and lymphocytes/monocytes ratio (LMR) were also retrieved. Subpopulations with frequency &lt;1% were normalized for total CD3+ cells. Results: From October 2020 to January 2024, 134 patients were enrolled and 115 completed NAT (85.8%). Fifty-one (38,1%) had adequate samples for analysis, 16 (31,4%) with hormone receptor positive HER2 negative BC (HR+HER2-), 15 (29,4%) with HER2+, and 20 (39,2%) with triple negative BC (TN). At baseline, patients with TNBC had the lowest NLR (p=0.018) and lowest senescent CD4+CD28- (p=0.042). Associations with pCR are shown in the Table. Overall, LMR associated with increased pCR (OR 1.34 [95% CIs 1.00-1.89]), and NLR with decreased pCR (OR 0.67 [0.39-1.04]). Both associations were driven by HR+ status (interaction p = 0.061 and 0.060). Senescent CD4+ predicted lower pCR in both HR-HER2+ (OR 0.10 [0.01-0.36]) and TNBC (OR 0.10 [0.01-0.5]). In TNBC, exhausted CD8+ predicted higher pCR (OR 1.78 [1.08-3.79]). When assessed separately in patients who received NAT with or without pembrolizumab, exhausted CD8+ remained predictor of pCR in chemotherapy + pembrolizumab (OR 1.84 [1.03-5.00]), but not with chemotherapy alone (p=0.203). The dynamics of paired pre-NAT and post-NAT TNBC samples revealed significant differences. Senescent CD4+ increased after chemotherapy, but not with chemotherapy + pembrolizumab (p=0.007). Pembrolizumab was associated with depletion of PD1-positive CD8+, while chemotherapy alone was not (p=0.020). Conclusions: The characterization of circulating T lymphocytes could help identify patients who benefit more in terms of pCR from specific NATs, including chemoimmunotherapy. [Table: see text]

BLU-222, an investigational, oral, potent, and highly selective CDK2 inhibitor (CDK2i), as monotherapy in patients (pts) with advanced solid tumors and in combination with ribociclib (RIBO) and fulvestrant (FUL) in HR+/HER2− breast cancer (BC).

1056 Background: CDK2 is implicated in CDK4/6 inhibitor (CDK4/6i) resistance in hormone receptor-positive/human epidermal growth factor receptor-2–negative (HR+/HER2−) BC. In addition, amplification and overexpression of cyclin E1 gene ( CCNE1), which leads to hyperactivation of cyclin E/CDK2 and CDK2 dependence, is associated with shorter survival in multiple aggressive cancers. CDK2 inhibition is thus an attractive novel anticancer approach. BLU-222 is an investigational, oral, potent, selective CDK2i in clinical development showing promise as a monotherapy and combination therapy. Methods: VELA (NCT05252416) is an international, open-label, phase 1/2 study evaluating BLU-222 safety and efficacy through dose escalation following a Bayesian Optimal Interval design. BLU-222 BID was administered in continuous 28-day cycles as monotherapy or in combination with RIBO + FUL. In monotherapy cohorts, pts with advanced relapsed/recurrent cancer were enrolled regardless of CCNE1 status. A combination cohort enrolled pts with HR+/ HER2− BC whose disease had progressed after treatment with a CDK4/6i. Results: As of January 22, 2024, 64 pts were included in the safety population: 53 in monotherapy cohorts (50-800 mg BID), 11 in the combination cohort (100-200 mg BID + 400 mg RIBO + 500 mg FUL). Median age was 63 y (range, 21-85); 88% were female. Most frequent cancer types in monotherapy cohorts were BC (32%, 17/53), ovarian (21%, 11/53), endometrial (8%, 4/53), and uterine (8%, 4/53). Pts had a median of 5 prior lines of therapy (LoT). Maximum tolerated dose had not been reached as of the data cutoff. With monotherapy, the most common treatment-emergent adverse events (TEAEs; ≥15%) included gastrointestinal events (nausea, diarrhea, vomiting), fatigue, anemia, photophobia, and hypokalemia. Dose-limiting toxicities occurred in 2 pts, 1 with grade 3 nausea at 800 mg BID and 1 with grade 3 blurred vision/photophobia at 600 mg BID; both improved after dose reduction. Increasing doses of BLU-222 monotherapy were associated with decreased TK1 activity and pRb. Eleven HR+/HER2− BC pts with a median of 5 prior LoT received BLU-222 with RIBO + FUL but have limited follow-up. The initial cohort of BLU-222 with RIBO + FUL was well tolerated. Updated combination data will be presented at the meeting. Conclusions: BLU-222 monotherapy was generally well tolerated in unselected heavily pretreated pts. In addition to encouraging safety, markers of cell cycle modulation and antitumor activity were seen. The initial cohort of BLU-222 with RIBO + FUL exhibited no additional safety concerns. Together, these data demonstrate the clinical potential of BLU-222 in CDK2-vulnerable tumors. Enrollment is ongoing for dose escalation and optimization. Clinical trial information: NCT05252416 .

Are we ready to use PSMA as a theranostic biomarker in clinical practice for patients with breast cancer?

e13114 Background: Subtype classification for breast cancer (BC) patients is important for risk-stratification. Unfortunately, this parameter is not able to discriminate perfectly between high- and low-risk disease and the identification of an accurate biomarker to determine aggressiveness is still a clinical need. Prostate-specific membrane antigen (PSMA) could be important given that it has been reported to be expressed in BC tumor cells and even more in endothelial cells of tumor vessels. Methods: We analyzed 101 BCs of whom 22 luminal A, 34 Luminal B, 22 HER2 positive and 23 triple negative (TN) BC to assess whether PSMA expression by immunohistochemistry was different in tumor subtypes and was related to ki67 expression and stromal (tumour-infiltrating lymphocytes) TILs. PSMA positivity was calculated as the number of positive vessels on 10 fields at 40X magnifications. Kruskal Wallis’s test was used to assess difference in PSMA positivity among BC subgroups and Dunn’s test was performed for post-hoc comparisons; Spearman’s rho coefficient was calculated to analyze the correlation among PSMA, KI67 and TILs. Results: The median age at diagnosis of BC patients was 66 (min-max: 25-87 years). Seventy (69.3%) patients had ER&gt;0 and 64 (63.4%) had PgR&gt;0. The ductal histotype was present in 92 patients (91%). The majority of the patients had grade 3 tumors (55.4%). Considering the number of positive vessels, our results showed that median PSMA was higher in TNBC compared to Luminal A, Luminal B and HER2 positive tumors (p&lt;0.001, p=0.001 and p=0.041, respectively). Ki67 was higher in TNBC compared to Luminal A, Luminal B and HER2 positive tumors (p&lt;0.001, p&lt;0.001 and p=0.001, respectively). We saw a correlation between PSMA and ki67, especially in HER2 positive tumors (p&lt;0.001), while a correlation between PSMA and TILs was observed in Luminal A (p=0.028). The analysis of PSMA expression on the lymph nodes showed the same trend observed for the primary tumors given that it was higher in TNBC compared to HER2 positive and luminal cancers. Conclusions: Our results suggest that PSMA could be used as a theranostic biomarker in BC considering that it is highly expressed in more aggressive tumors and the possibility to treat PSMA expressing patients for anti-angiogenesis and/or radionuclide treatment.

Therapeutic response and outcomes with less common breast cancer subtypes in the I-SPY trial 2011-2022.

582 Background: Uncommon histologies are over-represented among high-risk breast cancer (BC) and denote an area with limited trial data and of significant unmet medical need. To better understand trial outcomes in this group and identify signals of tumor responsiveness, we report pathologic complete response (pCR) and early event-free survival (EFS) by disease subtype in the I-SPY2 trial. Additionally, the I-SPY2 trial currently utilizes a combination of tumor molecular signature and receptor status to determine response predictive subtype (RPS) first developed from 987 I-SPY2 patients (1). We report disease response rates for those who received what is now known to be optimal RPS guided therapy. Methods: The I-SPY2 platform trial tests novel agents given neo-adjuvantly with a chemotherapy backbone in high-risk BC (HER2 positive, triple negative and high molecular risk estrogen receptor positive BC). Histologic images of research biopsies, local biopsy and surgical pathology reports were reviewed centrally by I-SPY pathologists. Receptor subtype distribution and pCR rates were summarized. EFS was estimated using the Kaplan Meier method. Association between pCR and EFS was evaluated using the Cox proportional hazard model with significance assessed by the log rank test. Results: 144/2118 (7%) of I-SPY2 participants were identified with metaplastic (60), lobular (55), mucinous (9), micropapillary (8), neuroendocrine (4) and other (8) BCs. Tumor receptor status, pCR rate and EFS by tumor type are shown in the Table. For the full cohort, pCR was associated with better EFS (hazard ratio (95% CI): 0.12 (0.02 - 0.88), p = 0.01). Within metaplastic (metapBC) 11/32 (34%) and 5/28 (18%) patients had a pCR with or without checkpoint blockade, respectively. By RPS group, 9 of 18 (50%) (13 metapBC, 3 other, 2 lobular) in the HER2-Immune+ group who received RPS optimized therapy had a pCR. In this group 6/13 (46%) with metapBC had a pCR. In the HER2+ driven RPS groups, pCR rate in the HER+HER2orBasal was 88% (7/8) and 0% (0/3) in the HER2+Luminal. Conclusions: High pCR rates observed in metapBC and other among subsets of often difficult to treat BC subtypes support novel approaches and provide a roadmap for future study of uncommon BCs. Outcomes were improved when therapy matched RPS vulnerabilities. Participants presenting with uncommon BC subtypes will be prospectively identified in the I-SPY2.2 trial to further develop effective approaches for this group. 1. Wolf et al, Cancer Cell 2022. Clinical trial information: NCT01042379 . [Table: see text]

Exploring the Clinical Impact of RANK Pathway Inhibition in Advanced Breast Cancer: Insights From a Retrospective Study on CDK4/6 Inhibitors and Antiresorptive Therapy.

Breast cancer (BC) remains a significant health concern, particularly in advanced stages where the prognosis is poor. The combination of endocrine therapy (ET) with cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) has improved outcomes for advanced BC (aBC) patients. However, resistance to CDK4/6i remains a challenge, with no validated biomarkers to predict response. The receptor activator of the nuclear factor-kB (RANK) pathway has emerged as a key player in aBC, particularly in luminal BC. RANK overexpression has been associated with aggressive phenotypes and resistance to therapy. In view of these findings, we proceeded to investigate the potential involvement of the RANK pathway in luminal BC resistance to CDK4/6i. The objective was to evaluate the effectiveness of denosumab in increasing overall survival (OS) and progression-free survival (PFS). In this retrospective analysis, 158 BC patients with bone metastases were included. Patients with human epidermal growth factor receptor-2 (HER2)-negative and hormone receptor-positive BC who received palbociclib or ribociclib in addition to antiresorptive medication were included. Patients received either denosumab or zoledronic acid (ZA) therapy. The primary endpoint was OS, with PFS as a secondary endpoint. Although the PFS and OS of denosumab were better than ZA in this study, it did not show a significant difference between the two drugs. Meanwhile, mOS was not achievable in patients in the denosumab group, while it was 34.1 months in patients in the ZA group. The hazard ratio (HR) showed a significant improvement for the denosumab group in patients under 60 of age (HR: 0.33, p<0.01), patients with a score of 1 HER2 overexpression (HR: 0.09, p=0.01), and patients with resistant endocrine (HR: 0.42, p=0.02) compared to ZA. This study highlights the potential clinical relevance of the RANK pathway in BC treatment, and our findings suggest that denosumab may offer significant benefits in terms of PFS and OS for certain subgroups, particularly those with HER2 scores of 1, patients under 60, and those with endocrine-resistant BC. In conclusion, considering that RANK pathway status may be a predictive biomarker for CDK4/6i treatment and may cause treatment resistance, our results demonstrate the clinical relevance of the combination of CDK4/6i + ET with RANKL inhibition.

Identifying mutations in ctDNA to predict antibody-drug conjugate response in breast cancer.

e13074 Background: Metastatic breast cancer (mBC) is a complex disease, and outcomes remain poor because new therapies are needed. A new class of drugs, antibody-drug conjugate (ADC), has shown effectiveness across all breast cancer subtypes. Yet FDA- approval for these therapies is restricted only to HER2 and triple-negative subtypes. Therefore, we urgently need to identify which patients, regardless of subtype, will respond to ADCs. The advent of circulating tumor DNA (ctDNA) offers a unique noninvasive method to capture breast cancer (BC) heterogeneity. Recently, ctDNA testing has been employed in clinical practice to guide targeted therapies for mBC, particularly in cases of hormone receptor positive (HR+) disease with mutations in PIK3CA and ESR1. The clinical implications to predict response to ADC therapy in BC remains unclear. Here we test the hypothesis that ctDNA can detect mutations that predict response to novel ADCs. Methods: We analyzed a subset of patients from the Dallas Metastatic Breast Cancer Study comprised of patients with mBC who underwent ctDNA testing using the Tempus xF liquid biopsy ctDNA sequencing panel. The data was analyzed from a single academic medical center between the initial year of ctDNA collection in 2019 to 2023. We identified detectable mutations from patients and addressed a relationship by using Metascape. Relevant signaling pathways were identified: APOBEC, ErbB signaling, p53 and Ras-MAPK pathway. Patients with triple negative, HER2, and HR BC were examined for ADC response and associated mutations. Survival analyses were estimated using Kaplan-Meier and Gehan Breslow Wilcoxon test for statistical analysis. Results: We identified 43 patients with HR+ mBC who had at least one mutation within the Ras-MAPK pathway and 10 of 43 received ADC therapy. Median survival of patients who received ADC therapy 58 months (n=10) vs not receiving ADC therapy 33 months (n=33) (p &lt; 0.05). Of the ten patients who received ADC treatment, 60% had 1+ HER2 staining on tissue biopsy. 70% of patients received Trastuzumab deruxtecan (T-DXd) and 30% received Sacituzumab govitecan (SG). SG was given to patients with negative HER2 staining on biopsy. Patients with at least one mutation within ABOBEC, ErbB signaling, and p53 pathways did not have statistically significant differences in mOS. Conclusions: In HR+ mBC, detection of mutated genes associated with the Ras-MAPK pathway by ctDNA was associated with a more favorable response when treated with ADCs. These findings are exciting because HR+ BCs are being targeted with ADCs regardless of HER2 or TROP2 expression, highlighting the need for new biomarkers to distinguish which HR+ patients to treat. Our retrospective analysis findings are limited by the number of patients with ctDNA testing and also timing of testing. Further studies are needed to solidify the observed correlation between Ras-MAPK pathway mutations and favorable response to ADC treatment.

Multilevel factors associated with delays to neoadjuvant chemotherapy among young adults with operable breast cancer.

11091 Background: Breast cancer (BC) rates are increasing in young adults (YAs: age 18-39) and this population may experience unique barriers to treatment initiation. We identified factors associated with treatment initiation delays in a cohort of YAs with operable BC who received neoadjuvant chemotherapy (NACT). Methods: Using the National Cancer Database, we identified YAs diagnosed with non-metastatic BC from 2010-2020 who received NACT. We grouped patients by receptor status and clinical stage: 1) Hormone Receptor positive/HER-2 negative (HR+/HER2-) and were lymph node (LN) LN+; 2) HER-2 positive (HER2+) cT2+ or LN+; and 3) triple negative BC (TNBC) cT2+ or LN+. Primary outcome was delayed treatment initiation, defined as &gt; 60 days from diagnosis date to NACT. Multivariable (MV) logistic regression was used to model factors associated with delay and adjusted for sociodemographic, clinical, and facility-level factors. We also examined factors associated with delays by tumor type. Results: Of 23,078 included patients, 62% were non-Hispanic White (NHW) and 74% had private insurance. By tumor type, 28% (n=6,350) were ER/PR+, 39% (n=8,921) were HER2+, and 34% (n=7,807) had TNBC. Most patients were treated at academic comprehensive cancer programs (ACCP) or comprehensive community cancer programs (CCCP) (40% and 34%). Treatment delays were observed among 7% of patients (n=1,638) across all tumor types. In MV analysis, non-Hispanic Black (NHB) and Hispanic YAs had 2-fold higher odds of delays compared with NHW YAs. YAs with low-income had higher odds of delays compared with higher income (OR=1.41), and YAs with private insurance had lower odds of delays compared with Medicaid (OR=0.54). YAs treated at any non-ACCP facility were less likely to experience delays. The results were similar for each tumor type. Conclusions: While the overall incidence of delays was low, significant racial, ethnic, and institutional-level treatment initiation disparities were observed among YAs receiving NACT for BC. [Table: see text]

Delays in receipt of neoadjuvant chemotherapy compared to upfront surgery in patients with operable breast cancer.

e13561 Background: Delays in time from breast cancer (BC) diagnosis to BC treatment initiation (BCTI) including upfront breast surgery (UBS) or neoadjuvant chemotherapy (NACT), can negatively impact BC survival. We evaluated odds of delay in BCTI among patients (pts) who received NACT compared to pts who received UBS. Methods: We conducted a retrospective cohort study using the National Cancer Database. Eligibility included age ≥18 years, diagnosis of non-metastatic BC between 1/1/2010 – 12/31/2020, who were treated with NACT followed by surgery or UBS followed by adjuvant chemotherapy (AC). Pts who did not receive NACT or UBS within 180 days of diagnosis were excluded. The cohort was stratified by first BC treatment (NACT or UBS), and time to NACT (TTNACT) or time to surgery (TTS) was recorded for each patient in days. Pts were categorized into sub-cohorts by receptor status and clinical stage: 1) Hormone Receptor positive/HER-2 negative (HR+/HER2-) lymph node (LN)+; 2) HER-2 positive (HER2+) cT2+ or LN+; and 3) triple negative BC (TNBC) cT2+ or LN+. Logistic regression adjusted for demographic, socioeconomic, and tumor characteristics was used to identify delays in BCTI &gt; 60 days. Multiple imputation was used for missing data. Inverse probability treatment weighting (IPTW) was done as a sensitivity analysis. Results: We identified 218,049 eligible pts, 75% were White, 18% were Black, and 8.6% were Hispanic. Median age was 53 years (range 18-90). There were 145,697 (67%) pts who received NACT with median TTNACT of 32 days (range 0-180), and 9.8% had a delay &gt; 60 days (Table). There were 72,353 (33.0%) pts who received UBS followed by AC, with a median TTS of 33 days (range 0-180), and 13% with a delay &gt; 60 days. In multivariable analysis, pts who received UBS had higher odds of BCTI delays compared to NACT, with OR 1.50 (95%CI 1.42-1.57) [HR+/HER2-], OR 1.49 (95%CI 1.41-1.58) [HER2+], and OR 1.26 (95%CI 1.18-1.34) [TNBC]. Results from IPTW analysis were similar, groups were well balanced, and pts who received UBS had higher odds of BCTI OR 1.50 (95%CI 1.44-1.57) [HR+/HER2-], OR 1.75 (95%CI 1.67-1.83) [HER2+], and OR 1.46 (95%CI 1.38-1.53) [TNBC]. Conclusions: Among high clinical risk BC patients who received surgery and chemotherapy, those who underwent NACT were less likely to experience delays in BCTI compared to pts who received UBS first. Among eligible pts, use of NACT may reduce delays in BCTI. [Table: see text]

Access to germline testing and prevalence of somatic mutations in patients with breast cancer from disadvantaged areas: A single-center study.

e13750 Background: Socioeconomic disparities affect clinical outcomes in several malignancies including breast cancer (BC). The Area Deprivation Index (ADI) is a tool used to classify regions based on socioeconomic factors, including employment, education, housing, and poverty. Here, we investigate ADI among patients (pts) with BC seen at Roswell Park Comprehensive Cancer Center and its association with recurrence free survival (RFS), time to next treatment (TNT), overall survival (OS), and access to somatic mutation via next-generation sequencing (NGS) and germline testing of BC pts. Methods: We conducted a retrospective analysis of 409 pts diagnosed with stages 1-3 and de-novo stage 4 BC from 2014 to 2018. ADI scores were derived from patients' home addresses using www.neighborhoodatlas.medicine.wisc.edu and categorized into four quartiles: Q1 (80-100%), Q2 (60-79%), Q3 (40-59%), and Q4 (0-39%) with Q1 representing areas with highest deprivation. Demographic and clinicopathological characteristics were summarized by ADI. Kruskal-Wallis and Chi-square was used for comparing continuous and categorical variables respectively. Results: Among 409 pts, 92% were female, 77% White, and 10% Black. 30% (n=123/409) lived in the most disadvantaged area Q1, 26% (106/409) Q2, 26% (104/409) Q3, and 12% (51/409) Q4, and 6% (25/409) unknown. 72% pts were hormone receptor positive, 14% HER2+, and 14% triple negative BC. No significant differences were noted in the racial distribution, employment, comorbidities, smoking, screening mammogram, type of insurance, BC stage and subtype, and adherence to therapy by ADI. Access to germline testing was significantly lower among pts from Q1 and Q2: (68/232 or 28%) vs. (65/156 or 42%) from Q3 and Q4, p= 0.03. There was no difference in RFS and OS by ADI. There was a trend towards decreased TNT (9 vs. 11 months, p=0.4) among BC pts living in areas with higher vs. lower ADI (&gt;60% vs &lt;60%). Notably, among stage 4 pts, in disadvantaged areas with ADI &gt;60%, there was higher prevalence of Estrogen Receptor1(ESR1) 72% (8/11) vs. 27% (3/11) and TP53 75% (9/12) vs. 25% (3/12) somatic mutations compared to less disadvantaged areas with ADI &lt;60%, p= 0.08 and 0.04, respectively. Conclusions: Our study shows disparities in access to germline testing, with lower rates among pts from more deprived areas. Moreover, somatic testing results show distinct mutational profiles across different ADI groups, suggesting potential impact of ADI on somatic characteristics. Larger studies are needed to investigate the association of ADI with somatic mutation burden of BC.

Clinical features of breast cancer in Ashkenazi Jewish carriers of the two founder BRCA1 pathogenic variants.

e12557 Background: Germline pathogenic variants (PVs) in BRCA1 and BRCA2 are the most common cause of hereditary breast and ovarian cancer. Carriers have a significantly elevated risk of developing breast cancer (BC) and ovarian cancer (OC) compared to the general female population. Two prevalent PVs in Ashkenazi Jews (AJ) in the BRCA1 gene are 185delAG and 5382insC. This study aims to compare clinical features of disease between the PV carrier groups. Methods: Data was collected retrospectively on 282 BC patients who were carriers of 5382insC or 185delAG, treated in Hadassah and Shaare Zedek Medical Centers between the years 1978 and 2021. Data collected included features such as age at disease onset, staging at diagnosis, additional malignancies or recurrence of disease, pathological features such as hormone receptor status and HER2 status (tumor subtype), and treatments. Disease characteristics and outcomes were compared. Results: There were 207 carriers of the 185delAG PV, while 75 carried the 5382insC PV. Amongst carriers of 185delAG, vs. 5382InsC, 58.1% vs. 35.8% (p&lt;0.01) had triple negative BC (TNBC), while 28.2% vs. 52.6% (p&lt;0.01) had hormone positive BC, respectively (Table). There was no significant difference in disease-free or overall survival, even after adjusting for age, stage and other potential confounders. Although it appeared that 5382insC carriers suffered a higher rate of OC (14% vs. 9.6%), and that 185delAG had a higher rate of non-OC malignancies (8.2% vs. 4%), these differences did not reach statistical significance. Conclusions: Our study suggests that 5382insC and 185delAG differ in their patterns of disease. Despite the lower rates of TNBC, 5382insC carriers had similar survival to 185delAG carriers. This could suggest that the hormone receptor positive disease amongst 5382InsC carriers had a less favorable course of disease, with a similar outcome as in those with TNBC. Further studies are warranted to better understand this pattern of disease aggression. [Table: see text]