ER-negative Status Research Articles

Assessing the Effectiveness of Simple Surgical Excision in Breast Cyst Management: Outcomes, Recurrence, and Postoperative Complications

Background: Breast cysts are common benign tumors that are frequently treated surgically to avoid problems and recurrence. Analyzing this strategy helps to maximize results. Objectives: To evaluate the effectiveness of simple surgical excision for treatment of breast cysts focusing on outcomes, recurrence rates, postoperative complications, and multiple biomarkers. Methods: Current prospective observational study was conducted with 150 female patients who underwent simple surgical excision of breast cysts from September 2023 to September 2024. Recurrence rates, postoperative complications, cosmetic outcomes and the relationship between biomarker profiles and recurrence were evaluated in patients and ER, PR, HER2, Ki-67, p53 and BCL-2 were assessed with immunohistochemistry. All data were analyzed using the chi-square test for categorical variables and independent t- tests for continuous variables with (P < 0.05) considered statistically significant. Results: Within 12 month follow up period, 8 patients (5.3%) had a repeat cyst. Ki-67 expression (>20%) was significantly associated with recurrence (P = 0.03), p53 overexpression (P = 0.04), and BCL-2 positivity (P = 0.02). There was no significant association with recurrence of ER, PR, HER2 and triple negative status. Seventeen patients (11.3%) had postoperative complications, most commonly wound infection (4.0%, P = 0.03). Cosmetic outcomes were generally favorable, however, patients reported lower overall satisfaction with the cosmetic outcomes in association with recurrence or complications (P = 0.04). Conclusions: Breast cysts can be successfully treated with simple surgical excision, which has good cosmetic results and a low recurrence rate. Larger cysts raise the likelihood of seroma with controllable consequences, BCL-2 provides protection, and biomarkers such as Ki-67 and p53 indicate high-risk instances.

Are the Common Genetic 3'UTR Variants in ADME Genes Playing a Role in Tolerance of Breast Cancer Chemotherapy?

We studied the associations between 3'UTR genetic variants in ADME genes, clinical factors, and the risk of breast cancer chemotherapy toxicity. Those variants and factors were tested in relation to seven symptoms belonging to myelotoxicity (anemia, leukopenia, neutropenia), gastrointestinal side effects (vomiting, nausea), nephrotoxicity, and hepatotoxicity, occurring in overall, early, or recurrent settings. The cumulative risk of overall symptoms of anemia was connected with AKR1C3 rs3209896 AG, ERCC1 rs3212986 GT, and >6 cycles of chemotherapy; leukopenia was determined by ABCC1 rs129081 allele G and DPYD rs291593 allele T; neutropenia risk was correlated with accumulation of genetic variants of DPYD rs291583 allele G, ABCB1 rs17064 AT, and positive HER2 status. Risk of nephrotoxicity was determined by homozygote DPYD rs291593, homozygote AKR1C3 rs3209896, postmenopausal age, and negative ER status. Increased risk of hepatotoxicity was connected with NR1/2 rs3732359 allele G, postmenopausal age, and with present metastases. The risk of nausea and vomiting was linked to several genetic factors and premenopausal age. We concluded that chemotherapy tolerance emerges from the simultaneous interaction of many genetic and clinical factors.

Tumor enhancement and shrinkage pattern in dynamic contrast-enhanced magnetic resonance imaging for predicting pathologic complete response after human epidermal growth factor receptor 2 (HER2)-targeted therapy in breast cancer.

Targeted therapy with neoadjuvant chemotherapy for patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer has increased the rates of pathological complete response (pCR) and breast preservation surgery and improved the overall disease-free survival rate. This study aimed to determine whether tumor enhancement and shrinkage patterns in dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) can predict the efficacy of targeted therapy in patients with HER2-positive breast cancer and differentiate pCR from non-pCR. The data of 64 patients with HER2-positive breast cancer who received targeted therapy prior to surgery were retrospectively collected. All patients had complete postoperative pathological data. The pretreatment evaluation of the tumor enhancement pattern and the shrinkage pattern after two treatment cycles were assessed. The difference in the enhancement and shrinkage patterns between the pCR and non-pCR groups was evaluated via the χ2 test. Logistic regression analysis was used to assess the value of enhancement and shrinkage patterns for predicting pCR in patients with HER2-positive breast cancer. There were statistically significant differences in tumor size, estrogen receptor (ER) status, lymph node metastasis, enhancement pattern, and shrinkage pattern between the pCR and non-pCR cases. Patients with a tumor size ≤20 mm were likely to achieve pCR. ER status, lymph node metastasis, and enhancement and shrinkage patterns each had good precision for predicting pCR, and the combination of enhancement and shrinkage patterns had the highest prediction accuracy. Multivariate logistic regression analysis indicated that only enhancement pattern had a significant predictive value. Among patients with HER2-positive breast cancer, those with tumor size ≤20 mm, ER-negative status, no lymph node metastases, and mass enhancement and concentric shrinkage patterns are more likely to achieve pCR. Mass enhancement combined with concentric shrinkage had the highest accuracy in predicting pCR, indicating that preoperative imaging may be useful for guiding clinical decisions regarding targeted treatments.

Predictors of pathological complete response to neoadjuvant treatment in invasive breast cancer with different human epidermal growth factor receptor 2 (HER2) subcategories.

Among human epidermal growth factor receptor 2 (HER2)-positive breast cancer patients who receive anti-HER2 treatment, a noteworthy correlation between pathological complete response (pCR) and longer survival has been observed. The rate of pCR varies with the tumor's degree of HER2 protein expression. The aim of this study was to assess the correlations between clinicopathological characteristics, magnetic resonance imaging (MRI) parameters, and pCR in breast cancer with different HER2 subcategories. A total of 281 invasive breast cancer patients diagnosed with HER2-positivity were included. HER2-positive translated to immunohistochemistry (IHC) 3+ or IHC 2+/fluorescence in situ hybridization (FISH)(+). All enrolled patients underwent baseline MRI examination and received neoadjuvant chemotherapy, dual anti-HER2 therapy, and subsequent therapeutic surgery from January 2021 to May 2022. A logistic regression model was used to evaluate the effects of covariates on pCR. Compared to the IHC 2+/FISH(+) group, patients with IHC 3+ tumors had a higher pCR rate (58.1% vs. 26.7%, P<0.001), clinical stage (58.6% vs. 40%, P=0.038), apparent diffusion coefficient (ADC) value (0.96 vs. 0.88 mm2/s, P=0.004), and were more likely to be estrogen receptor (ER) negative (55.9% vs. 31.1%, P=0.002) and progesterone receptor (PR) negative (72.5% vs. 46.7%, P=0.001). In both groups, univariate analysis showed that the pCR group more often had ER-negative and PR-negative status than the non-pCR group (P<0.001). The final multivariable analysis showed that ER-negativity was associated with pCR in the IHC 2+/FISH(+) group (P=0.004). ER-negativity and the longest diameter were two independent predictors of pCR in the IHC 3+ group (P<0.001 for ER, P=0.026 for longest diameter). The IHC 3+ group had a higher pCR rate than the IHC 2+/FISH(+) group. Along with clinicopathological characteristics, MRI parameters were supplemental predictors of pCR, particularly in IHC 3+ patients.

Immunohistochemical Expression of Cyclooxygenase 2 (COX-2) as a Prognostic Marker and Its Correlation With Clinicopathological Parameters in Breast Cancer.

Introduction Breast cancer is considered the most common cancer among women. According to the literature, cyclooxygenase-2 (COX-2) expression in breast carcinoma is associated with aggressive tumor biology and acts as an independent prognostic marker. As COX-2 is a newly identified marker, studies are required to understand its immunoexpression and correlation with hormone receptor status and other prognostic factors, which helps in the therapeutic management of patients. Hence, this study evaluates the expression of COX-2 in breast carcinoma. Methods A hospital-based cross-sectional study was done on 55 mastectomy specimens collected at the Histopathology and Surgical Pathology Section of the Department of Pathology. The patient's age, histological type, tumor size, lymph node status, histological grade, and vascular invasion were noted. Immunohistochemical staining for estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2/neu protooncogene (HER2/neu), and COX-2 markers was performed, and its results were compared with these clinicopathological and prognostic parameters. Results were subjected to statistical analysis. Results COX-2 expression was seen in 37 out of 55 cases (67.2%). Expression of COX-2 showed a statistically significant correlation with vascular invasion, ER-negative status, and PR-negative status. No statistical association was found between other parameters like age, tumor size, histological type, histological grade, lymph node status, and HER2/neu status. Conclusion The expression of COX-2 correlated strongly with well-established poor prognostic markers, such as vascular invasion, ER-negative status, and PR-negative status. Thus, expression of COX-2 suggests aggressive tumor biology, and it can be used as an independent prognostic marker.

The impact of loco-regional treatment modality on the outcomes in breast cancer patients younger than forty years of age

PurposeTo determine the impact of the loco-regional treatment modality, on the loco-regional recurrence (LRR) rates and overall survival (OS) in breast cancer patients younger than 40 years.MethodsData of 623 breast cancer patients younger than 40 years of age were retrospectively reviewed. Patients were stratified according to the locoregional treatment approach into three groups: the mastectomy group (M), the mastectomy followed by radiation therapy group (MRX) and the breast conservative therapy group (BCT).ResultsMedian follow-up was 72 months (range, 6-180). Two hundred and nine patients were treated with BCT, 86 with MRM and 328 with MRX. The 10-year rate LRR rates according to treatment modality were: 13.4% for BCT, 15.1% for MRM and 8.5% for MRX (p 0.106). On univariate analysis, T stage (p 0.009), AJCC stage (p 0.047) and Her 2 status (p 0.001) were associated with LRR. Ten-year overall survival (OS) was 72.7% (78.5% in the BCT group, 69.8% in the MRM group and 69.8% in the MRX group, p 0.072).On Univariate analysis, age < 35 (p 0.032), grade III (p 0.001), N3 stage (p 0.001), AJCC stage III (p 0.005), ER negative status (0.04), Her 2-status positive (0.006) and lack of chemotherapy administration (p 0.02) were all predictors of increased mortality.ConclusionFor patients younger than 40 years of age, similar LRR and overall survival outcomes were achieved using BCT, M or MRX. Young age at diagnosis should not be used alone in recommending one loco-regional treatment approach over the others.

Clinicopathological Significance of Cyclin-Dependent Kinase 2 (CDK2) in Ductal Carcinoma In Situ and Early-Stage Invasive Breast Cancers.

Cyclin-dependent kinase 2 (CDK2) is a key cell cycle regulator, with essential roles during G1/S transition. The clinicopathological significance of CDK2 in ductal carcinomas in situ (DCIS) and early-stage invasive breast cancers (BCs) remains largely unknown. Here, we evaluated CDK2's protein expression in 479 BC samples and 216 DCIS specimens. Analysis of CDK2 transcripts was completed in the METABRIC cohort (n = 1980) and TCGA cohort (n = 1090), respectively. A high nuclear CDK2 protein expression was significantly associated with aggressive phenotypes, including a high tumour grade, lymph vascular invasion, a poor Nottingham prognostic index (all p-values < 0.0001), and shorter survival (p = 0.006), especially in luminal BC (p = 0.009). In p53-mutant BC, high nuclear CDK2 remained linked with worse survival (p = 0.01). In DCIS, high nuclear/low cytoplasmic co-expression showed significant association with a high tumour grade (p = 0.043), triple-negative and HER2-enriched molecular subtypes (p = 0.01), Comedo necrosis (p = 0.024), negative ER status (p = 0.004), negative PR status (p < 0.0001), and a high proliferation index (p < 0.0001). Tumours with high CDK2 transcripts were more likely to have higher expressions of genes involved in the cell cycle, homologous recombination, and p53 signaling. We provide compelling evidence that high CDK2 is a feature of aggressive breast cancers. The clinical evaluation of CDK2 inhibitors in early-stage BC patients will have a clinical impact.

Abstract PS08-01: Antibody-Drug Conjugates (ADCs) in Breast Cancer: Real World Analysis of Outcomes

Abstract Methods: We estimated the distribution of progression-free survival (PFS), overall survival (OS), and time to treatment failure (TTF) using the Kaplan-Meier method. Differences in survival curves between groups categorized by initial ADC treatment and subsequent ADC treatments were assessed using the log-rank test. Cox proportional hazards regression models were employed to evaluate the association between each survival outcome and various measures of interest, such as age, gender, race, number of prior lines of treatment, hormone receptor status, and HER2 status. Results: The analysis included a total of 469 breast cancer patients, with the distribution of clinical characteristics summarized in Table 1. The median age at the start of ADC treatment was 50 years (range: 20-85). Among the patients, 263 patients (56%) received SC as their initial ADC treatment, while 44% received T-DXd. Additionally, 29 patients received both ADCs during metastatic treatment. The median follow-up time for all patients was 7.9 months (range: 0.1- 39.1). Out of the total patient population, 29% died, while 71% were still alive at the last follow-up. The median OS for all patients was 21.6 months. Median OS of patients receiving SC or T-DXd as their initial ADC treatment, was 14 and 37.1 months, respectively. Patients who received both SC and T-DXd had a median OS of 26.1 months. The median PFS for all patients was 6.0 months. Patients initially treated with SC had a median PFS of 4.7 months, whereas those treated with T-DXd had a median PFS of 9.0 months. In patients who received both, median of PFS was 4.9 months for T-DXd after SC, and 5.0 months for SC after T-DXd. The median TTF for all patients was 6.1 months. Patients initially treated with SC had a median TTF of 4.7 months, while those treated with T-DXd had a median TTF of 9.0 months. In patients who received T-DXd after SC, TTF was 4.9 months and SC after T-DXd was 5.0 months. Clinician-judged responses were seen in 180 (74%)of patients with SC only, 80 (41%) with T-DXd only, 9 (100%) with SC as 2nd ADC and 20 (100%) with T-DXd as 2nd ADC. Furthermore, the analysis explored the association of OS, PFS, and TTF with various measures of interest, including age, gender, race, number of prior lines of treatment, type of treatment, hormone receptor status, HER2 status, Ki67, and best response to ADC. Some notable associations were observed, such as ER-positive status being associated with marginally longer OS compared to ER-negative status (median 24.7 vs. 16.4 months; p=0.06), and HER2-positive status being associated with longer PFS compared to HER2-negative status (median 14.2 vs. 5.4 months; p&amp;lt; 0.001). However, these associations should be interpreted cautiously as they were obtained from univariate analysis. Conclusions: Overall, these results highlight the significant differences in survival outcomes between different ADC treatments in breast cancer patients, likely due to differing patient characteristics. Distribution of clinical characteristics across ADCs Citation Format: Akshara Singareeka Raghavendra, Zhongya Wang, Roland Bassett, Debu Tripathy. Antibody-Drug Conjugates (ADCs) in Breast Cancer: Real World Analysis of Outcomes [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PS08-01.

Global untargeted and individual targeted plasma metabolomics of breast cancer recurrence modified by hormone receptors.

Breast cancer is a heterogeneous and complex etiological disease. Understanding perturbations of circulating metabolites could improve prognosis. We recruited breast cancer patients from Kaohsiung Medical University (KMU) to perform untargeted (case-control design) and targeted (patient cohort) metabolomics analyses in the discovery and validation phases to evaluate interaction effects between clinical factors and plasma metabolites using multivariable Cox proportional hazards model. In the discovery phase, partial least squares-discriminant analysis (PLS-DA) showed that plasma metabolites were significantly different between recurrent and non-recurrent breast cancer patients. Metabolite set enrichment analysis (MSEA) and metabolomic pathway analysis (MetPA) showed that valine, leucine, and isoleucine degradation was the significant pathway, and volcano plot showed significant ten upregulated and two downregulated metabolites between recurrent and non-recurrent cases. Combined with receiver operating characteristic (ROC) curve and biological significance, creatine, valine, methionine, and mannose were selected for the validation phase. In this patient cohort with 41 new-recurrent vs. 248 non-recurrent breast cancer cases, followed for 720.49 person-years, compared with low level of valine, high valine level was significantly negatively associated with recurrent breast cancer (aHR: 0.36, 95% CI: 0.18-0.72, P = 0.004), especially in ER-negative and PR-negative status. There were interaction effects between valine and ER (Pinteraction = 0.006) as well as PR (Pinteraction = 0.002) on recurrent breast cancer. After Bonferroni correction, stratification effects between valine and hormone receptors were still significant. Our study revealed that plasma metabolites were significantly different between recurrent and non-recurrent patients, proposing therapeutic insights for breast cancer prognosis.

Risk factors and survival of triple-negative breast cancer among breast cancer patients: Ten-year cross-sectional study in the southwestern Iranian population.

Breast cancer results from genetic and epigenetic mutations, contributing significantly to cancer-related morbidity and mortality. This study aimed to determine the prevalence and survival rates of triple-negative breast cancer (TNBC) among breast cancer patients in southwestern Iran over a ten-year period. This retrospective cross-sectional study aims to assess prognostic factors associated with survival in women diagnosed with breast cancer in Iran's southwestern region over a ten-year period (2007-2017). Data were collected from patients who visited the Clinical Oncology Department at Golestan Hospital in Ahvaz (the breast cancer center of the Southwestern country). The study enrolled women diagnosed with TNBC using a census method and data from medical records. The primary outcome (survival rates) and secondary outcomes (demographic data, diagnostic stages, and three receptors estrogen receptors [ER], progesterone receptor [PR], human epidermal growth factor receptor 2 [HER2] status) were collected. Breast cancer was diagnosed in 2641 women over ten years; TNBC was diagnosed in 227 individuals (8.59%). Statistical analysis revealed a significant correlation between negative ER status and TNBC (p > 0.05). Furthermore, the prevalence of TNBC differed significantly from that of other types of breast cancer (p = 0.0001). The variables of age, HER2, PR, and TNBC grade did not differ significantly (p > 0.05). The overall disease-free survival rate over 5 years was 88.1%, while the rate for individuals without recurrence was 77.97%. This study highlights a differentially low incidence of TNBC in the southwestern part of Iran when compared to other regions; genetic or epigenetic influences may explain this discrepancy. ER-negative status is a crucial prognostic indicator in diagnosing TNBC. The incidence of this disease is expected to rise by 100% in 2 years and 77.97% in 5 years.

Gene Signature Associated with Nervous System in an Experimental Radiation- and Estrogen-Induced Breast Cancer Model.

Breast cancer is frequently the most diagnosed female cancer in the world. The experimental studies on cancer seldom focus on the relationship between the central nervous system and cancer. Despite extensive research into the treatment of breast cancer, chemotherapy resistance is an important issue limiting the efficacy of treatment. Novel biomarkers to predict prognosis or sensitivity to chemotherapy are urgently needed. This study examined nervous-system-related genes. The profiling of differentially expressed genes indicated that high-LET radiation, such as that emitted by radon progeny, in the presence of estrogen, induced a cascade of events indicative of tumorigenicity in human breast epithelial cells. Bioinformatic tools allowed us to analyze the genes involved in breast cancer and associated with the nervous system. The results indicated that the gene expression of the Ephrin A1 gene (EFNA1), the roundabout guidance receptor 1 (ROBO1), and the kallikrein-related peptidase 6 (KLK6) was greater in T2 and A5 than in the A3 cell line; the LIM domain kinase 2 gene (LIMK2) was greater in T2 than A3 and A5; the kallikrein-related peptidase 7 (KLK7), the neuroligin 4 X-linked gene (NLGN4X), and myelin basic protein (MBP) were greater than A3 only in T2; and the neural precursor cell expressed, developmentally down-regulated 9 gene (NEDD9) was greater in A5 than in the A3 and E cell lines. Concerning the correlation, it was found a positive correlation between ESR1 and EFNA1 in BRCA-LumA patients; with ROBO1 in BRCA-Basal patients, but this correlation was negative with the kallikrein-related peptidase 6 (KLK6) in BRCA-LumA and -LumB, as well as with LIMK2 and ROBO1 in all BRCA. It was also positive with neuroligin 4 X-linked (NLGN4X) in BRCA-Her2 and BRCA-LumB, and with MBP in BRCA-LumA and -LumB, but negative with KLK7 in all BRCA and BRCA-LumA and NEDD9 in BRCA-Her2. The differential gene expression levels between the tumor and adjacent tissue indicated that the ROBO1, KLK6, LIMK2, KLK7, NLGN4X, MBP, and NEDD9 gene expression levels were higher in normal tissues than in tumors; however, EFNA1 was higher in the tumor than the normal ones. EFNA1, LIMK2, ROBO1, KLK6, KLK7, and MBP gene expression had a negative ER status, whereas NEDD9 and NLGN4X were not significant concerning ER status. In conclusion, important markers have been analyzed concerning genes related to the nervous system, opening up a new avenue of studies in breast cancer therapy.

A SOX10+/AR- immunoprofile may identify a subset of low positive ER carcinomas with a wider range of ER expression

BackgroundInvasive breast carcinomas (IBC) that strongly express SOX10 are almost always negative for androgen receptor (AR). Furthermore, this SOX10+/AR- subset of IBC is nearly always estrogen receptor and progesterone receptor negative (ER-/PR-), being most commonly seen in triple negative breast carcinomas (TNBC), but also in a small subset of HER2+/ER-/PR- IBC. Following our previous work demonstrating the expression of SOX10 in a subset of IBC with “low positive” ER expression (i.e. 1–10 % ER+ staining based on CAP guidelines, here referred to as “ER-low”), we sought to investigate the expression of both SOX10 and AR in a larger cohort of ER-low tumors. As our previous work also revealed occasional SOX10 expression in IBC with >10 % ER+ staining, we also included tumors with any percentage of ER staining, as long as the staining intensity was weak (this subset is referred to as “ER-weak”). MethodsWe screened cases of HER2-/ER+ IBC diagnosed at our institution over a 10 year period, identified both ER-low and ER-weak tumors and stained both groups with SOX10 and AR. ResultsStrong SOX10 expression was seen in 12/25 (48 %) ER-low tumors and 13/24 (54 %) ER-weak tumors. ER staining in the SOX10+ subset of ER-weak tumors ranged from 15 %−80 % (median 25 %). As expected, AR was negative in all but 1 of the SOX10+ tumors in both groups. While case numbers in these groups were too small for a meaningful statistical analysis, we did note that all SOX10+/AR- tumors within both the ER-low and ER-weak groups were histologic grade 3. ConclusionThe presence of a SOX10+/AR- profile in a significant subset of ER-low tumors confirms the findings of our previous work and provides further support for the proposed functionally ER negative status of this group. Furthermore, the fact that the same SOX10+/AR- profile is seen in a roughly equal subset of ER-weak tumors suggests that a wider range of ER staining may be acceptable as “low positive” in SOX10+/AR- tumors, as long as the ER staining is of weak intensity. However, given the small number of cases in this single institution study, we emphasize the need for larger studies to establish the biological and clinical significance of this tumor subset.

Analysis of Breast Cancer Family History, Estrogen Receptor Status, and Breast Cancer Outcomes in Sweden

ImportanceBreast cancer (BC), the most prevalent cancer among women globally, is a heterogeneous disease, with prognosis differing by estrogen receptor (ER) status. Having a family history of BC increases the risk of BC; however, it is unclear whether family history is associated with the prognosis of overall and ER-specific BC.ObjectiveTo assess whether a family history of BC is associated with the prognosis of overall and ER-specific BC.Design, Setting, and ParticipantsThis cohort study was based on data from several national registers in Sweden. All female residents of Stockholm who were born after 1932; had their first BC diagnosis between January 1, 1991, and December 31, 2019; and had at least 1 identified female first-degree relative (FDR) were included. Women who were diagnosed with other types of cancer before their BC diagnosis, were older than 75 years at diagnosis, or had distant metastasis at diagnosis were excluded. A total of 28 649 women were included. Data were analyzed from January 10, 2022, to December 20, 2022.ExposuresFamily history of BC, defined as 1 or more female FDRs diagnosed with BC.Main Outcomes and MeasuresPatients were followed up until BC-specific death, censoring, or end of follow-up on December 31, 2019. The role of family history in BC-specific mortality was investigated using flexible parametric survival models among the full cohort, ER-positive subgroup, and ER-negative subgroup, adjusting for demographic characteristics, tumor characteristics, and treatments received.ResultsAmong 28 649 patients, the mean (SD) age at BC diagnosis was 55.7 (10.4) years; 19 545 (68.2%) had ER-positive BC, and 4078 (14.2%) had ER-negative BC. Overall, 5081 patients (17.7%) had at least 1 female FDR diagnosed with BC, while 384 (1.3%) had a family history of early-onset BC (FDR diagnosed before age 40 years). During the follow-up period (median [IQR], 8.7 [4.1-15.1] years), 2748 patients (9.6%) died of BC. Multivariable analyses revealed that having a family history of BC was associated with a lower risk of BC-specific death among the full cohort (hazard ratio [HR], 0.78; 95% CI, 0.65-0.95) and the ER-negative subgroup (HR, 0.57; 95% CI, 0.40-0.82) in the first 5 years, after which no association was observed. However, having an early-onset family history was associated with a higher risk of BC-specific death (HR, 1.41; 95% CI, 1.03-2.34).Conclusions and RelevanceIn this study, patients with a family history of BC did not necessarily have a worse prognosis. Those with ER-negative status and a family history of BC had more favorable outcomes in the first 5 years after diagnosis, possibly due to enhanced motivation to receive and adhere to treatment. However, patients with a family history of early-onset BC had worse survival, suggesting that genetic testing of newly diagnosed patients with early-onset family history may provide useful information to aid treatment and future research.

Risk of estrogen receptor-specific breast cancer by family history of estrogen receptor subtypes and other cancers.

The extent to which the risk of estrogen receptor (ER)-specific breast cancer is associated with ER status of breast cancer and other cancers among first-degree relatives is unclear. This population-based cohort included 464 707 cancer-free women in Stockholm, Sweden, during 1978-2019. For ER-negative and ER-positive breast cancers, we estimated hazard ratios (HRs) associated with ER status of female first-degree relatives with breast cancer and of other cancers in all first-degree relatives. Associations between ER-negative and ER-positive status by family cancer history were estimated using logistic regression in a case-only design. Women with familial ER-positive breast cancer had 1.87 times (95% confidence interval [CI] = 1.77 to 1.97) higher risk of ER-positive subtype, whereas the corresponding hazard ratio for ER-negative was 2.54 (95% CI = 2.08 to 3.10) when having familial ER-negative breast cancer. The risk increased with an increasing number of female first-degree relatives having concordant subtypes and younger age at diagnosis (Ptrend <.001 for both). Nonbreast cancers among first-degree relatives were associated with both ER-positive (HR = 1.14, 95% CI = 1.10 to 1.17) and ER-negative (HR = 1.08, 95% CI = 1.01 to 1.16) breast cancers. Compared with women with ER-positive breast cancer, women with ER-negative breast cancer were more likely to have family history of liver (odds ratio [OR] = 1.33, 95% CI = 1.05 to 1.67), ovary (OR = 1.28, 95% CI = 1.01 to 1.61), and testicle cancer (OR = 1.79, 95% CI = 1.01 to 3.16) but less likely to have family history of endometrial cancer (OR = 0.77, 95% CI = 0.60 to 1.00) and leukemia (OR = 0.72, 95% CI = 0.56 to 0.91). Risk of ER-specific breast cancer differs according to ER status of female first-degree relatives with breast cancer and some other cancers of first-degree relatives. This family history information should be considered in the individual risk prediction for ER subtypes.

PREDICTING RESPONSE TO NEOADJUVANT CHEMOTHERAPY IN OPERABLE BREAST CANCER: ROLE OF ER, PR, HER2 AND KI-67 INDEX

Background: Neoadjuvant (anterior or pre-operative) chemotherapy for operable breast cancer helps in down-staging of the tumor and increases the rate of breast conservation surgery. Factors that identify individuals who benet from chemotherapy have not been clearly established. This study was conducted to assess the role of estrogen receptor, progesterone receptor, HER2 and Ki-67 index in predicting response to a standard anthracycline and taxane-based chemotherapy. Methods: The study included 62 women with clinical tumor stage 1-3 and nodal stage 0 or 1. All women received preoperative anthracycline and taxane-based chemotherapy followed by surgery. Clinical and pathological response was assessed using World Health Organization (UICC) and Chevallier's criteria respectively. Results: Clinical and pathological complete response rates were 40.3% and 17.7% respectively. The pathological complete response was highest in HER2-enriched patients (45.45%) while basal-like and luminal B subtypes accounted for 27.27% each. Among those that achieved pathological complete response, 90% had Ki-67 &gt;20, 81.8% had grade 3, 72.7% had ER negative status, 81.8% had PR negative status, 63.6% had HER2 positive status. However, there was no statistically signicant association between preoperative clinical tumor size(p=0.98), ER(p=0.053), PR(p=0.17), HER2(p=0.17), Ki-67 index(p=0.26) and pathological complete response. Conclusion: Ahigh pathological complete response was observed in tumors with high grade, high proliferative activity (high Ki-67), ER/PR negative status, HER2 over-expressing tumors and aggressive molecular subtypes such as basal-like and HER2-enriched breast cancer. However, none of these pre-chemotherapy factors showed statistically signicant association with pathological complete response.

High VISTA expression is linked to a potent epithelial-mesenchymal transition and is positively correlated with PD1 in breast cancer.

Breast cancer is the most common type of tumor in women worldwide. Immune checkpoint inhibitors, particularly anti-PDL1, have shown promise as a therapeutic approach for managing this disease. However, this type of immunotherapy still fails to work for some patients, leading researchers to explore alternative immune checkpoint targets. The Ig suppressor of T cell activation domain V (VISTA) has emerged as a novel immune checkpoint that delivers inhibitory signals to T cells and has demonstrated encouraging results in various cancers. Our study investigated the association of VISTA expression with clinicopathological parameters in breast cancer patients, its involvement in the Epithelial-Mesenchymal-Transition (EMT) process, and its correlation with PD1 expression. Transcriptomic analysis revealed that VISTA was associated with lobular and metaplastic histological type, tumor size, lymph node status, ER and PR negative status, and the TNBC molecular subtype. Furthermore, VISTA expression was strongly associated with an immunosuppressive tumor microenvironment. Immunohistochemistry analysis corroborated the transcriptomic results, indicating that VISTA was expressed in most immune cells (94%) and was significantly expressed in breast cancer tumor cells compared to matched adjacent tissues. Our study also showed for the first time that VISTA overexpression in breast cancer cells could be associated with the EMT process. Additionally, we identified a positive correlation between VISTA and PD-1 expression. Together, these results highlight the immunosuppressive effect of VISTA in breast cancer patients and suggest that bi-specific targeting of VISTA and PD-1 in combination therapy could be beneficial for these patients.

Abstract P4-03-20: Association between reproductive factors (parity and age first full term birth) and the frequency of estrogen receptor negative breast cancer according to age at diagnosis

Abstract Background: The frequency of early estrogen receptor (ER)-negative breast cancers (BC) decreases with increasing age at diagnosis (Partridge P, JCO 2016). Giving birth is generally considered a protective factor for the occurrence of BC in a woman’s lifetime. However, for up to more than 20 years following childbirth, BC risk may be higher. This appears to be due to an increase in hormone receptor-positive BC, especially in women older at the time of 1st childbirth (Nichols HB, Ann Int Med 2019). This means that the ER-negative BC are relatively less frequent in these 2 decades after delivery. In this study, we aimed at retrospectively investigating the impact of parity and age at first full term pregnancy (FFTP) on the frequency of ER-negative BC according to the age at diagnosis in a large institutional cohort of patients diagnosed with BC. Patients and Methods: We considered all patients diagnosed and/or treated with early BC in UZ Leuven between January 2000 and November 2020. ER-negativity was defined as &amp;lt; 1% positive cells. Age at diagnosis was subdivided in categories of 5 years. Parous women could be having a low (1 or 2 children) or high parity (&amp;gt; 2 children) and age of FFTP was arbitrarily divided into &amp;lt; or ≥ 27 years of age. BMI was considered a possible confounder and was corrected for. A logistic regression model was used for data analysis with ER-negative status as binary outcome and FFTP class and multiparity as explanatory variables. To test whether the difference in ER-negative proportions between FFTP classes depends on multiparity, we modelled the interaction between multiparity and FFTP class. Results: We included 9955 consecutive female patients after excluding missing values. 8358 out of 9955 women had at least 1 child (84%). In our study population, parity as such was not an independent variable for BC subtype. Women with a FFTP ≥ 27y as compared to those with a FFTP &amp;lt; 27y were less likely to have an ER-negative BC. The p-value for the interaction term between high parity (&amp;gt;2 children) and FFTP class equals p= 0.0044. Hence, there is statistical evidence to suggest that the differences between FFTP categories with regards to ER-negative BC may depend on multiparity. Table 1 shows a lower incidence of ER-negative BC in the FFTP ≥ 27y group compared to the FFTP &amp;lt; 27y group in case of high parity. Table 2 shows the absolute proportion. These results seem to be independent of BMI. Conclusion: Women with a FFTP at 27 years of age or older and more than 2 children have proportionally less ER-negative type breast cancers as compared to women with a FFTP before 27 years of age. This difference between FFTP classes is not observed in absence of high parity. Table 1: effect of FFTP class by multiparity Table 2: proportion of ER-negative breast cancer subtype Citation Format: Maja Vangoitsenhoven, Evert Theys, Karen Van Baelen, Annouschka Laenen, Christine Desmedt, Giuseppe Floris, Hans Wildiers, Kevin Punie, Sileny Han, Thaïs Baert, Frédéric Amant, Ann Smeets, Ines Nevelsteen, Rani Vanhoudt, Patrick Neven. Association between reproductive factors (parity and age first full term birth) and the frequency of estrogen receptor negative breast cancer according to age at diagnosis [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-03-20.

Grade and Estrogen Receptor Expression Identify a Subset of No Specific Molecular Profile Endometrial Carcinomas at a Very Low Risk of Disease-Specific Death

Endometrial carcinoma (EC) can be divided into 4 prognostic molecular subtypes, and no specific molecular profile (NSMP) type is the most commonly occurring type (∼50%). Although described as having an intermediate to favorable prognosis, this subtype encompasses pathologically and molecularly diverse tumors. We aimed to identify factors associated with outcomes within the NSMP ECs that might be used to stratify prognosis and direct treatment. Clinicopathologic, immunohistochemical, and genetic features of a large series of NSMP EC were used to identify parameters that could identify the subset associated with a very favorable outcome (disease-specific death rate <5% at 5 years, termed low-risk NSMP). A total of 1110 NSMP ECs were profiled. In a univariate analysis, stage, grade, lymphovascular invasion, estrogen receptor (ER) and progesterone receptor (PR) expression, L1CAM overexpression, and mutations in PIK3CA were associated with disease-specific survival. Two critical features, grade and ER expression, identified a low-risk NSMP subset (grade 1-2, ER-positive [>1%], 84% of cases), which showed a 5-year disease-specific death rate of 1.6% across all stages and 1.4% within stage I. The remaining cases (high-risk NSMPs, grade 3, and/or ER-negative status) were responsible for most of the disease-specific deaths (disease-specific death rate at 5 years, 22.9%; hazard ratio compared with that of low-risk NSMPs: 16.3; 95% CI, 8.4-31.7). Within NSMP EC, the low-risk and high-risk categories were of prognostic significance independent of the stage on a multivariate analysis. Low-grade and ER-positive NSMP ECs are a homogeneous low-risk group associated with an exceptionally favorable prognosis in which de-escalation and/or endocrine therapy strategies can be applied. Grade 3 and/or ER-negative status identifies a high-risk NSMP subset, including rare high-grade histotypes (eg, clear cell, dedifferentiated, and mesonephric-like), responsible for most NSMP-related deaths. Subclassification of NSMPs allows for the category of low-risk EC molecular subtypes to be dramatically expanded because it now includes both POLEmut and the much more common low-risk NSMP EC.

Prediction of Clinical Molecular Typing of Breast Invasive Ductal Carcinoma Using 18F-FDG PET/CT Dual-Phase Imaging

To investigate the diagnostic value of Fluorine-18-labeled 2-fluoro-2-deoxy-D-glucose positron emission tomography and computed tomography (18F-FDG PET/CT) dual-phase imaging for the different molecular subtypes of invasive ductal carcinoma of the breast. Clinical imaging data of 164 women with invasive ductal carcinoma of the breast confirmed by pathology who underwent 18F-FDG PET/CT dual-phase imaging were retrospectively analyzed. The maximum standard uptake values (SUVmax) of the early and delayed phases of the lesion were measured and recorded as SUVmax1 and SUVmax2, respectively, and the retention index (RI) was calculated. We analyzed the change rule of SUVmax1, SUVmax2, and RI for the different molecular subtypes and molecular marker expression groups. The diagnostic threshold of different molecular marker expression status was determined using receiver operating characteristic curve analysis. SUVmax1 and SUVmax2 were highest in the TNBC group and lowest in the luminal A group (p<0.001). TNBC and HER2 overexpression groups had higher RI than the luminal A and B groups (p<0.001), with no significant difference between the TNBC and HER2 overexpression groups or between the luminal A and B groups (p=0.640 and 0.345, respectively). The ER- and PR-negative groups had significantly higher SUVmax1, SUVmax2, and RI than the PR-positive group (p<0.001). The HER2-positive group had higher SUVmax1 and SUVmax2 than the negative group (p<0.001). The Ki67 overexpression group had higher SUVmax1 and SUVmax2 levels than the low expression group (p<0.001). There was no significant difference in RI between HER2-positive and negative groups or between Ki67 high and low expression groups (p=0.904 and 0.216, respectively). For ER-negative and positive expression status, the maximum area under the curve (AUC) of SUVmax2 was 0.852, diagnostic threshold was 10.87, sensitivity was 79.6%, and specificity was 74.5%. For PR-negative and positive expression status, the AUC of SUVmax2 was 0.858, diagnostic threshold was 10.45, sensitivity was 83.1%, and specificity was 75.3%. For HER2-negative and positive expression status, the AUC of SUVmax1 was 0.714, diagnostic threshold was 9.28, sensitivity was 79.6%, and specificity was 60.9%. For Ki67 high- and low expression status, the AUC of SUVmax2 was 0.915 at maximum, diagnostic threshold was 10.21, sensitivity was 83.4%, and specificity was 93.9%. 18F-FDG PET/CT dual-phase imaging facilitates the prediction of the expression of molecular markers and subtypes of invasive ductal carcinoma of the breast and the development of more tailored treatment plans for patients with this disease.

A prognostic nomogram based on risk assessment for invasive micropapillary carcinoma of the breast after surgery.

Invasive micropapillary carcinoma (IMPC) is one of the rare subtypes of breast cancer. This study aimed to explore a predictive nomogram model for IMPC prognosis. A total of 1855 IMPC patients diagnosed after surgery between 2004 and 2014 were identified from the Surveillance, Epidemiology and End Results (SEER) database to build and validate nomogram. A nomogram was created based on univariate and multivariate Cox proportional hazards regression analysis. Receiver operating characteristic (ROC) curves were used to demonstrate the accuracy of the prognostic model. Decision curve analysis (DCA) was performed to evaluate the safety of the model in the range of clinical applications, while calibration curves were used to validate the prediction consistency. Cox regression analysis indicated that age ≥62 at diagnosis, negative ER status, and tumor stage were considered adverse independent factors for overall survival (OS), while patients who were married, white or of other races, received chemotherapy or radiotherapy, had a better postoperative prognosis. The nomogram accurately predicted OS with high internal and external validation consistency index (C index) (0.756 and 0.742, respectively). The areas under the ROC curve (AUCs) of the training group were 0.787, 0.774 and 0.764 for 3, 5 and 10 years, respectively, while those of the validation group were 0.756, 0.766 and 0.762, respectively. The results of both DCA and calibration curves demonstrated the good performance of the model. A nomogram for IMPC of the breast patients after surgery was developed to estimate 3, 5 and 10 years-OS based on independent risk factors. This model has good accuracy and consistency in predicting prognosis and has clinical application value.