ER-negative Patients Research Articles

Abstract A004: Validation of the PREDICT breast version 3.0 prognostic tool in the US breast cancer patients

Abstract PREDICT Breast v3 is the latest version of a prognostic tool designed to predict the treatment responses for early invasive breast cancer patients. It was developed using data from approximately 35,000 women diagnosed between 2000 and 2018 in the United Kingdom. However, its performance in the United States (US) population is unknown. This study aims to validate PREDICT Breast v3 using the newly released Surveillance, Epidemiology, and End Results (SEER) outcome data for US breast cancer patients and to address potential health disparities. We selected over 860,000 female patients diagnosed with primary breast cancer between 2000 and 2021 and followed for at least 5 years from the SEER database. The model’s performance was measured by calibration and discrimination; comparing predicted and observed 5-, 10- and 15-year breast cancer-specific survival outcomes and determining discrimination through the area under the receiver-operator curves (AUC). PREDICT Breast v3 demonstrated good calibration and discrimination for both short- and long-term up breast cancer-specific mortality in US populations. The predicted 10-year breast cancer-specific mortality differed from observed by 11% in ER-positive and 6 % in ER-negative patients. The AUCs for 15-year breast cancer-specific mortality were 0.81 for ER-positive patients and 0.76 for ER-negative patients. When stratified by race and ethnicity, the model showed strong performance in Non-Hispanic Asians ER-positive patients, despite being originally developed based on the UK population. These results are consistent with previous validations in Malaysia, Japan, and other Asian countries for PREDICT Breast v2. However, the model poorly estimated the number of deaths in Non-Hispanic Black individuals for both ER-positive and ER-negative. In conclusion, this study marks the first validation of PREDICT Breast v3 in the US and demonstrates that it is a reliable and generalizable tool, capable of providing longer term follow-up time up to 15 years for a wide and diverse population. Citation Format: Yi-Wen Hsiao, Paul Pharaoh, Pei-Chen Peng. Validation of the PREDICT breast version 3.0 prognostic tool in the US breast cancer patients [abstract]. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr A004.

Low cytoplasmic NUB1 protein exerts hypoxic cell death with poorer prognosis in oestrogen receptor negative breast cancer patients

Current prognostic biomarkers fall short in stratifying Oestrogen receptor (ER)-negative breast cancer patients regarding tumour progression risk at diagnosis. The role of AIPL1 in activating its tumour suppressor client protein, NEDD8 Ultimate Buster-1 (NUB1) remains unknown in cancer. Our study demonstrated how downregulated AIPL1 results in the deactivated NUB1 protein under hypoxic conditions. We examined the AIPL1-NUB1 pathwayin vitro using cell lines i.e. MCF-7, MDA-MB-231, RCC4 etc. NUB1 expression was assessed using Oncomine, and cBioPortal was performed to assess NUB1′s prognostic significance in human cancers. In the John Radcliffe Hospital cohort (n = 122), immunohistochemistry analysis revealed downregulated AIPL1 (Log2 fold change=-0.28; p < 0.001) and upregulated NUB1 transcripts (Log2 fold change=0.59; p < 0.001) compared to adjacent normal tissues. In severe chronic hypoxia, multimerised AIPL1 localisedin the cytoplasm while NUB1 protein migrated to the nucleus, where the absence of NUB1 nuclear localisation led to cell cycle arrest. Biopsies showed that patients with lower cytoplasmic NUB1 expression (n = 57) had poorer overall survival compared to those with higher cytoplasmic expression (n = 57), HR=1.78; 95 % CI=1.01–3.35, p = 0.048. Low NUB1 protein levels in both normoxic and hypoxic conditions were associated with cell cycle arrest and upregulation ofp21 and p27 in breast cancer cell lines, correlating significantly withpoorer survival outcomes in all breast cancer and ER-negative breast cancer patients.

Immune and Gene-expression Profiling in Estrogen Receptor Low and Negative Early Breast Cancer.

The cut-off of < 1% positive cells to define estrogen receptor (ER) negativity by immunohistochemistry (IHC) in breast cancer (BC) is debated. We explored the tumor immune microenvironment and gene-expression profile of patients with early-stage HER2-negative ER-low (ER 1-9%) BC, comparing them to ER-negative (ER < 1%) and ER-intermediate (ER 10-50%) tumors. Among 921 patients with early-stage I-III, ER ≤ 50%, HER2-negative BCs, tumors were classified as ER-negative (n = 712), ER-low (n = 128), or ER-intermediate (n = 81). Tumor-infiltrating lymphocytes (TILs) were evaluated. CD8+, FOXP3+ cells, and PD-L1 status were assessed by IHC and quantified by digital pathology. We analyzed 776 BC-related genes in 116 samples. All tests were 2-sided at < 0.05 significance level. ER-low and ER-negative tumors exhibited similar median TILs, significantly higher than ER-intermediate tumors. CD8/FOXP3 ratio and PD-L1 positivity rates were comparable between ER-low and ER-negative groups. These groups showed similar enrichment in Basal-like intrinsic subtypes and comparable expression of immune-related genes. ER-low and ER-intermediate tumors showed significant transcriptomic differences. High TILs (≥30%) were associated with improved relapse-free survival (RFS) in ER-low (5-year RFS 78.6% vs 66.2%, log-rank p = .033, hazard ratio (HR) 0.37 [95% CI 0.15-0.96]) and ER-negative patients (5-year RFS 85.2% vs 69.8%, log-rank p < .001, HR 0.41 [95% CI 0.27-0.60]). ER-low and ER-negative tumors are similar biological and molecular entities, supporting their comparable clinical outcomes and treatment responses, including to immunotherapy. Our findings contribute to the growing evidence calling for a reevaluation of ER-positive BC classification and management, aligning ER-low and ER-negative tumors more closely.

Insights into the performance of PREDICT tool in a large Mainland Chinese breast cancer cohort: a comparative analysis of versions 3.0 and 2.2.

PREDICT is a web-based tool for forecasting breast cancer outcomes. PREDICT version 3.0 was recently released. This study aimed to validate this tool for a large population in mainland China and compare v3.0 with v2.2. Women who underwent surgery for nonmetastatic primary invasive breast cancer between 2010 and 2020 from the First Affiliated Hospital of Wenzhou Medical University were selected. Predicted and observed 5-year overall survival (OS) for both v3.0 and v2.2 were compared. Discrimination was compared using receiver-operator curves and DeLong test. Calibration was evaluated using calibration plots and chi-squared test. A difference greater than 5% was deemed clinically relevant. A total of 5424 patients were included, with median follow-up time of 58 months (IQR 38-89 months). Compared to v2.2, v3.0 did not show improved discriminatory accuracy for 5-year OS (AUC: 0.756 vs 0.771), same as ER-positive and ER-negative patients. However, calibration was significantly improved in v3.0, with predicted 5-year OS deviated from observed by -2.0% for the entire cohort, -2.9% for ER-positive and -0.0% for ER-negative patients, compared to -7.3%, -4.7% and -13.7% in v2.2. In v3.0, 5-year OS was underestimated by 9.0% for patients older than 75 years, and 5.8% for patients with micrometastases. Patients with distant metastases postdiagnosis was overestimated by 10.6%. PREDICT v3.0 reliably predicts 5-year OS for the majority of Chinese patients with breast cancer. PREDICT v3.0 significantly improved the predictive accuracy for ER-negative groups. Furthermore, caution is advised when interpreting 5-year OS for patients aged over 70, those with micrometastases or metastases postdiagnosis.

Comprehensive analysis of the prognostic value of glutathione S-transferases Mu family members in breast cancer.

Breast cancer (BC) remains a significant public health concern globally, with a high number of reported cases and a substantial number of deaths every year. Accumulating reactive oxygen species (ROS) and oxidative stress are related to BC and the Glutathione S-transferases Mu (GSTM) family is one of the most important enzymatic detoxifiers associated with many cancers. In this study, UALCAN, Kaplan-Meier plotter, bc-GenExMiner, cBioPortal, STRING, Enrichr, and TIMER databases were employed to carry out a comprehensive bioinformatic analysis and provide new insight into the prognostic value of GSTMs in BC. GSTM2-5 genes in mRNA and protein levels were found to be expressed at lower levels in breast tumors compared to normal tissues, and reduction in mRNA levels is linked to shorter overall survival (OS) and relapse-free survival (RFS). The lower mRNA levels of GSTMs were strongly associated with the worse Scarff-Bloom-Richardson (SBR) grades (p < 0.0001). The mRNA levels of all five GSTMs were substantially higher in estrogen receptor (ER)-positive and progesterone receptor (PR)-positive compared to ER-negative and PR-negative BC patients. As well, when nodal status was compared, GSTM1, GSTM3, and GSTM5 were significantly higher in nodal-positive BC patients (p < .01). Furthermore, GSTM4 had the most gene alteration (4%) among other family members, and GSTM5 showed the strongest correlation with CD4+ T cells (Cor= .234, p = 2.22e-13). In conclusion, our results suggest that GSTM family members may be helpful as biomarkers for prognosis and as therapeutic targets in BC.

Capecitabine monotherapy as first-line treatment in advanced HER2-normal breast cancer - a nationwide, retrospective study.

The study utilized the Danish Breast Cancer Group (DBCG) database and was conducted retrospectively across all Danish oncology departments. Inclusion criteria were female patients, with HER2-normal advanced breast cancer treated with capecitabine monotherapy as the first-line treatment from 2010 to 2020. The primary endpoints were overall survival (OS) and progression-free survival (PFS). A total of 494 patients were included. Median OS was 16.4 months (95% confidence interval [CI]: 14.5-18.0), and median PFS was 6.0 months (95% CI: 5.3-6.7). Patients with estrogen receptor (ER)-positive disease had significantly longer OS (median: 22.8 vs. 10.5 months, p < 0.001) and PFS (median: 7.4 vs. 4.9 months, p = 0.003), when compared to ER-negative patients. Stratifying by age, patients under 45 years displayed a median PFS of 4.1 months, while those aged 45-70 years and over 70 years had median PFS of 5.7 and 7.2 months, respectively (p = 0.01). In this nationwide study, the efficacy of capecitabine as a first-line treatment for HER2-normal advanced breast cancer is consistent with other, mainly retrospective, studies. However, when assessed against contemporary and newer treatments, its effectiveness appears inferior to alternative chemotherapies or targeted therapies.

Abstract PO5-17-09: Event-free survival in HER2-low vs HER2-zero breast cancer patients submitted to neoadjuvant chemotherapy

Abstract Background: Breast cancer (BC) with low expression of HER2 (HER2-low) might constitute a group of tumors with unique clinical and biological characteristics. However, the prognostic impact of HER2-low status vs HER2-zero in terms of pathological complete response (pCR) and event-free survival (EFS) after neoadjuvant chemotherapy (NACT) remains controversial. The aim of this study was to evaluate pCR and EFS rates in HER2-low vs HER2-zero early BC patients treated with NACT. Methods: In this cross-sectional study, we analyzed 565 consecutive patients with HER2-low and HER2-zero early BC submitted to neoadjuvant therapy from 2017 to 2021 in a single academic center. Patients with biopsy-confirmed stage I-III BC, with HER2-low or HER2-zero status, submitted to locoregional therapy after NACT were included. Clinical and pathological characteristics, pathological response, treatment protocol and RFS were analyzed and considered for statistical analysis. HER2-low was defined by IHC 1+, or 2+ ISH non-amplified; HER2-zero was defined by IHC 0. Pathological response was determined locally, and pCR defined as the absence of residual invasive disease with or without ductal carcinoma in situ in the breast and axilla. EFS was defined as the time from diagnosis to distant recurrence, a second primary, or death from any cause, whichever occurred first. Results: 441 patients were included in the analysis, 236 (53.5%) patients with HER2-low tumors, and 205 (46.5%) with HER2-zero tumors. Overall, 279 (63.3%) were estrogen receptor (ER)-positive tumors, and 162 (36.5%) were ER-negative tumors. Among ER-positive tumors, 166 (59.5%) had HER2-low status, and 113 (40.5%) were HER2-zero. For the ER-negative subgroup, the corresponding rates were 70 (43.2%) and 92 (56.8%), respectively. Most patients had stage II-III BC (423/441; 96%), and 20.2% (89/441) had high nodal tumor burden. Many patients received anthracycline- and taxane-based NACT (425/441; 96.4%), and over 90% (148/162; 91.3%) of ER-negative patients received a platinum agent. The overall pCR rate were 18.1%. Among ER+ tumors, pCR rates were 6.4%, 6.0%, and 7.0% in the overall, HER2-low and HER2-zero tumors, respectively. In ER- tumors, the corresponding pCR rates were 38.3%, 35.7, and 40.2%, respectively. The differences in pCR rates between HER2-low and HER2-zero tumors were not statistically significant (ER-positive, p=0.724; ER-negative, p=0.559). After a median follow-up of 42 months, 90 EFS events occurred. In the HER2-low group there were 56 (23.7%) EFS events, and 34 (16.6%) EFS events in the HER2-zero (HR 1.19; 95% CI 0.77-1.82; p=0.427). Among 279 patients in the ER-positive group there were 48 events, 32 in the HER2-low subgroup and 16 in the HER2-zero group (HR 1.16; 95% CI 0.64-2.13; p=0.622). Among 162 ER-negative tumors there were 42 events, 24 in the HER2-low subgroup, and 24 in the HER2-zero subgroup (HR 1.56; 95% CI 0.84-2.88; p=0.158). NACT discontinuation occurred in 86 patients (ER-positive: 45, 16.1%; ER-negative: 41, 25.3%), mainly due to toxicity (anthracycline-taxane: 10.0%; platinum: 11.7%). Disease progression during NACT were reported in 6.8% (30/441) of patients. Conclusions: Our results show similar pCR rates and RFS among HER2-low and HER2-zero early BC patients after standard NACT, which are consistent with the current literature. Despite the predictive role of low HER2 expression in selecting patients for novel antibody-drug conjugates (ADCs) therapy, its prognostic value could not be confirmed. Citation Format: Guilherme Sartori, Susana Ramalho, Leonardo Roberto da Silva, Tomás Reinert, Mahira Lopes Da Rosa, Grazielle Morais Tavares, Vivian Vasconcelos, Higor Mantovani, Ana Elisa Ribeiro Da Silva Cabello, Guilherme Coelho, Jovana Mandelli, Facundo Zaffaroni, César Cabello, Carlos Barrios, Marcia Silveira Graudenz. Event-free survival in HER2-low vs HER2-zero breast cancer patients submitted to neoadjuvant chemotherapy [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-17-09.

Abstract PO4-06-05: The prognostic impact of age at diagnosis of metastatic breast cancer according to estrogen receptor status: a single-center, retrospective study

Abstract Background: Young age is associated with poor prognosis and aggressive biology in early breast cancer, especially in luminal subtypes. But the prognostic impact of age in metastatic breast cancer (MBC) is unclear. Also it is known that chemotherapy is more effective in estrogen receptor (ER)-negative tumors than in ER-positive tumors and young patients respond better to chemotherapy. The authors tried to evaluate the impact of age on disease outcome according to ER status. Methods: We collected individual patient data from January 2000 to December 2022 from the Ewha Womans University Mokdong Hospital. Total 419 ER-positive and 238 ER-negative patients who had been treated for MBC were included for analysis. We compared clinical characteristics and overall survival (OS) of patients among three age groups (&amp;lt; 35, 35 to 50 and &amp;gt;50 years) at MBC diagnosis in ER-positive and -negative tumors. Results: The proportion of patients aged &amp;lt; 35, 35-50 and &amp;gt; 50 years was 3.1%, 46.6% and 32.3% in ER-positive tumors, and 2.7%, 14.8% and 18.4% in ER-negative tumors. Although most characteristics of tumors according to age were comparable, bone metastasis was more common in patients aged 35-50 years than the other age groups in ER-positive (51.8% vs. 36.0% in &amp;gt;50 years, P=0.006) and time to first metastasis was shorter in younger patients in ER-negative tumors (72.2% between 6 and 24 months vs. 31.1% in patients &amp;gt;50 years, P=0.003). The median follow-up time was 65 months. Overall survival rate was not different according to age in ER-positive tumors (P=0.909). On the other hands, younger patients had a higher risk of death in ER-negative tumors (P=0.015). In multivariate analysis, young age at MBC diagnosis (&amp;lt; 35years) with short time to metastasis (6 to 24 months), visceral metastasis, triple negative breast cancer was correlated with poor overall survival in ER-negative tumors (P=0.014, HR 1.77). Conclusions: Young age at MBC diagnosis was associated with a higher risk of death in ER-negative tumors, not in ER-positive tumors. These observations may suggest that physicians should consider the impact of age at diagnosis of metastasis and time course of disease in evaluating survival potential and determining a treatment strategy in metastatic breast cancers. Citation Format: Joohyun Woo, Ahrong Ham, Sewon Lee, Ji Eun Lee, Soo Ji Hong, Haena Lee, Sungchan Gwark, Jun Woo Lee, Hyun Goo Kim, Jungmin Jo, Woosung Lim, Byung-In Moon, Sei Hyun Ahn, Hye Ah Lee, Kyoung Eun Lee. The prognostic impact of age at diagnosis of metastatic breast cancer according to estrogen receptor status: a single-center, retrospective study [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-06-05.

Independent Validation of the BRENDA-Score Breast Cancer Prognosis Prediction Tool In Chinese Patients

BackgroundThe BRENDA-Score was developed and used to predict the prognosis of patients with breast cancer (BC). This study was performed to validate the use of this tool in Chinese patients with primary invasive BC patients. MethodsPatients underwent surgery for BC from January 2009 to December 2016. Discrimination was assessed by the area under the receiver operating characteristic (ROC) curve (AUC). Calibrations were assessed by comparing predicted and observed 5-year and 10-year metastasis-free survival (MFS) in the overall cohort and patient subgroups. ResultsA total of 2029 BC patients were enrolled. Kaplan–Meier analysis revealed significant differences in MFS risk groups (log-rank test P < .01). ROC analysis showed good accuracy for 5-year MFS (AUC 0.779) and fair accuracy for 10-year MFS (AUC 0.728). The BRENDA-Score accurately predicted 5-year and 10-year MFS in the entire cohort and in all other predefined subgroups, except for the 5-year MFS in the subgroup aged<40 years, which was overestimated (differences between the predicted and observed MFS were 6.7%, P < .05). The 5-year MFS rates of ER- positive and ER-negative patients were 90.9% and 80.6%, respectively (P < .05). The 10-year MFS rates of ER-positive and ER-negative patients were 78.0% and 73.7%, respectively (P = .25). ConclusionsThe BRENDA-Score accurately predicted 5-year and 10-year MFS. The results showed good validity, transportability, and potential clinical value. However, the results for 5-years MFS should be interpreted carefully in patients aged <40 years. After 10 years the value of the ER as a prognostic factor was less important.

CD10 expression as a potential predictor of pathological complete response in ER-negative and triple-negative breast cancer patients treated with anthracycline-based neoadjuvant chemotherapy

BackgroundNeoadjuvant chemotherapy (NCT) can induce a pathological complete response (pCR) in breast cancer patients, leading to improved outcomes. However, predicting which patients will achieve pCR remains a challenge. CD10, a myoepithelial marker, has shown diagnostic and prognostic value in metastatic tumors. Its potential as a predictor of chemosensitivity to anthracycline-based NCT in breast cancer is unknown. AimThis retrospective study aimed to investigate the potential of CD10 cancer cell expression as a predictive marker of chemosensitivity in breast cancers treated with anthracycline-based neoadjuvant chemotherapy. MethodsWe analyzed 130 patients with invasive ductal carcinoma who received anthracycline-based NCT. CD10 expression was assessed by immunohistochemistry on pre-treatment biopsies. Statistical analysis evaluated the association between CD10 expression and pCR rates. ResultsUnivariate analysis revealed that ER-positive and CD10-negative tumors had lower pCR rates [OR 7.4830 (95% CI 2.7762–20.1699); p = 0.0001]. Multivariate analysis confirmed ER status as a strong predictor of poor response [OR 0.085 (95% CI 0.024–0.30); p < 0.001] and CD10 expression as a predictor of a favourable response [OR 0.11 (0.8–0.19); p = 0.049]. CD10 expression significantly predicted pCR in ER-negative cases [OR 0.1098 (0.0268–0.4503); p = 0.0022] and triple-negative breast cancer [OR 0.0966 (95% CI 0.0270–0.3462); p = 0.0003]. Concordance was observed between core biopsies and excised samples. ConclusionPositive CD10 cancer cell expression may predict increased response to anthracycline-based neoadjuvant chemotherapy in ER-negative and triple-negative breast cancer cases. Further research is needed to validate these findings in larger cohorts and determine the clinical utility of CD10 as a predictive marker.

Prognostic Value of IGFBP6 in Breast Cancer: Focus on Glucometabolism.

IGFBP6, a member of the IGF binding protein (IGFBP) family, is a specific inhibitor of insulin-like growth factor II (IGF-II) and can inhibit the growth of malignant tumors overexpressing IGF-II. Type 2 diabetes (T2D) is a basic disorder of glucose metabolism that can be regulated by IGF-related pathways. We performed bioinformatics analysis of the TCGA database to explore the possible mechanism of IGFBP6 in breast cancer (BC) metabolism and prognosis and collected clinical samples from BC patients with and without T2D to compare and verify the prognostic effect of IGFBP6. In our study, the levels of IGFBP1-6 were positively correlated with overall survival (OS) in patients with breast cancer. IGFBP6 was upregulated in estrogen receptor (ER)-positive BC, and ER-positive and progesterone receptor (PR) positive patients had a higher expression level of IGFBP6 than ER-negative and PR-negative patients. IGFBP6 could be used as an independent prognostic factor in BC. The expression of IGFBP6 was decreased in BC tissue, and BC tissue from patients with T2D had lower IGFBP6 expression levels than BC tissue from patients without T2D. IGFBP6 is mainly involved in the PI3K-Akt and TGF-β signaling pathways and tumor microenvironment regulation. In terms of metabolism, the expression of IGFBP6 was negatively correlated with that of most glucose metabolism-related genes. IGFBP6 expression was mainly correlated with mutations in TP53, PIK3CA, CDH1, and MAP3K1. In addition, the upregulation of IGFBP6 in BC increased the drug sensitivity to docetaxel, paclitaxel and gemcitabine. Overall, these results indicated that high expression of IGFBP6 is associated with a good prognosis in BC patients, especially in those without T2D. It is not only involved in the maintenance of the tumor microenvironment in BC but also inhibits the energy metabolism of cancer cells through glucose metabolism-related pathways. These findings may provide a new perspective on IGFBP6 as a potential prognostic marker for BC.

Immunolocalization of Cytoplasmic ER in ER-negative Breast Carcinoma as a Potent Favorable Prognostic Predictor.

It is known that estrogen receptor (ER) has extranuclear signaling functions in addition to classical genomic pathway, and estrogenic actions have been reported in ER-negative breast carcinoma cells. However, significance of cytoplasmic-ER immunoreactivity has not been reported in ER-negative breast carcinoma tissues. We immunolocalized cytoplasmic ER in 155 ER-negative breast carcinoma tissues and evaluated its clinicopathological significance including the prognosis. As a comparative cohort set, we also used 142 ER-positive breast carcinomas. Cytoplasmic-ER immunoreactivity was detected in the carcinoma cells, but not in the non-neoplastic mammary epithelium. Cytoplasmic-ER immunoreactivity was positive in the 35 out of 155 (23%) ER-negative breast carcinoma cases, whereas it was detected only in 2 out of 142 (1.4%) ER-positive cases. Cytoplasmic ER status was positively associated with cytoplasmic-PR status, but inversely associated with Ki67 labeling index or distant free-relapse survival rate. Moreover, cytoplasmic-ER status turned out to be an independent good prognostic factor for both distant relapse-free survival and breast cancer specific survival. These findings suggested that cytoplasmic ER plays important roles in the ER-negative breast carcinoma, and cytoplasmic ER is a potent good prognostic factor. Among the ER-negative breast cancer patients, clinical benefit of chemotherapy may be limited in the cytoplasmic-ER positive cases.

Evaluation of miRNA-200c and βIII tubulin as promising markers for clinical decision making in locally advanced breast cancer patients receiving taxanes therapy

BackgroundClinical management of locally advanced breast cancer (LABC) is a common clinical problem. Therefore, finding a good predictor for the efficacy of treatment is crucial. The miRNAs are small non-coding RNAs that play an important role in gene regulation of many biological processes. Class III tubulin (βIII tubulin) are dynamic fibrous cytoskeletal proteins that play a significant role in chromosome segregation during mitosis and meiosis and has been identified to participate in cell proliferation and cancer development. AimTo evaluate the role of miRNA-200c and βIII tubulin as promising markers for clinical decision making in locally advanced breast cancer patients receiving taxanes therapy. MethodsA retrospective study of paraffin sections of 143 female breast patients: 22 patients with benign breast diseases and 121 breast cancer patients receiving neoadjuvant taxane therapy divided to: 94 responder patients and 27 non responder patients. Patients were followed up from date of first diagnosis till end of the study. The expression level of miRNA 200c was evaluated using real time PCR and the expression level of βIII tubulin protein was immunohistochemically estimated. Results were correlated with response to neoadjuvant taxanes therapy. ResultsThe miRNA 200 c was significantly down regulated in patients responding to taxanes as compared with non-responders (p = 0.009). The βIII tubulin protein was significantly highly expressed in ER negative and PR negative breast cancer patients (p = 0.011, p = 0.053, respectively). It was significantly up regulated in triple negative and HER2 enriched (non luminal) cases and down regulated in luminal cases (p = 0.023). ConclusionThe results suggest miRNA 200c may be a predictive marker for response to neoadjuvant taxanes therapy in breast cancer patients, while βIII tubulin protein showed association with molecular subtypes of breast cancer namely luminal versus non luminal cases that may serve as an excellent marker for clinical decision making.

Prevalence of Androgen Receptor in Invasive Breast Cancer and Its Association with Clinicopathologic Features in East Azarbaijan Province of Iran: A Cross-Sectional Study.

Background: Breast cancer is the most common malignancy and the leading cause of cancer-related deaths in females. Accordingly, the evaluation of new prognostic markers and therapeutic targets is of vital importance. Here, we aimed to detect androgen receptor (AR) status and define its association with clinicopathologic parameters in patients with invasive breast cancer. Materials and Methods: In this study, AR status was studied in 104 patients with invasive breast carcinoma by immunohistochemistry. Besides, its association with clinicopathologic factors, i.e., age, menopausal status, tumor size, lymph node involvement, tumor stage, tumor grade and estrogen receptor (ER), progesterone receptor (PR), Her2/neu, Ki-67and P53 were investigated. Results: AR was positive in 84 patients (80.8%), and its expression in ER-positive (85.7%) and PR-positive (85.6%) patients were remarkably higher than in ER-negative (46.2%) and PR-negative (50%) patients (p= 0.001 and p=0.002, respectively). AR expression was noticeably lower in Her2/neu-positive (25%) patients compared to Her2/neu-negative (87.9%) ones (p=0.000). AR expression was also higher in patients with smaller, earlier stage, and low mitotically active tumors, but the association was not statistically significant. Conclusion: The expression of AR in patients with breast cancer was found to be high and its association with ER-positive, PR-positive, and HER2/neu-negative tumors was found to be significant. In that light, this receptor may play an important role in the determination of prognosis and targeted therapy in breast cancer.

Molecular features of androgen-receptor low, estrogen receptor-negative breast cancers in the Carolina breast cancer study

PurposeAndrogen receptor (AR) expression is absent in 40–90% of estrogen receptor (ER)-negative breast cancers. The prognostic value of AR in ER-negative patients and therapeutic targets for patients absent in AR remains poorly explored.MethodsWe used an RNA-based multigene classifier to identify AR-low and AR-high ER-negative participants in the Carolina Breast Cancer Study (CBCS; N = 669) and The Cancer Genome Atlas (TCGA; N = 237). We compared AR-defined subgroups by demographics, tumor characteristics, and established molecular signatures [PAM50 risk of recurrence (ROR), homologous recombination deficiency (HRD), and immune response].ResultsAR-low tumors were more prevalent among younger (RFD = + 10%, 95% CI = 4% to 16%) participants in CBCS and were associated with HER2 negativity (RFD = − 35%, 95% CI = − 44% to − 26%), higher grade (RFD = + 17%, 95% CI = 8% to 26%), and higher risk of recurrence scores (RFD = + 22%, 95% CI = 16.1% to 28%), with similar results in TCGA. The AR-low subgroup was strongly associated with HRD in CBCS (RFD = + 33.3%, 95% CI = 23.8% to 43.2%) and TCGA (RFD = + 41.5%, 95% CI = 34.0% to 48.6%). In CBCS, AR-low tumors had high adaptive immune marker expression.ConclusionMultigene, RNA-based low AR expression is associated with aggressive disease characteristics as well as DNA repair defects and immune phenotypes, suggesting plausible precision therapies for AR-low, ER-negative patients.

Abstract P6-01-15: Breast cancer patients with different hormone receptor subtypes receiving neoadjuvant chemotherapy (NAC) experience differential overall survival according to their resistance to NAC

Abstract Background: Response to neoadjuvant chemotherapy (NAC) is an indicator of outcomes and can be quantified as achievement of pathologic complete response (pCR) (absence of residual invasive disease in breast and lymph nodes) and residual percent cellularity. However, the significance of residual tumor cellularity post-NAC is not well understood. We assessed the impact of NAC-induced reduction in tumor cellularity among hormone receptor subtypes and the effect of these reductions on overall survival (OS). Methods: An IRB-approved retrospective review identified demographics, disease presentation, response to treatment, and outcomes. ER and PR status were categorized as low positive (1-9%), positive (≥ 10%) and negative. Treatment response was noted as percent residual cellularity (complete 0%, almost complete &amp;lt; 10%, good 10-30%, moderate &amp;gt;30-80% and poor &amp;gt;80%) in the surgical specimen and pathologic stage. We examined measures of response to NAC within breast tumor subtypes and the effect of these responses on associations with OS among hormone receptor subtypes. Results: The clinical series comprised 384 patients who received curative intent NAC. This series was diverse in presentation, displayed considerable variability in response to NAC (Table 1). 88 (23.6%) patients did not experience tumor down staging, and of those presenting with clinical nodal Stage 1 or higher (n=197), 94 (47.7%) did not experience nodal down staging. Although Triple Negative Breast Cancer (TNBC) status was not significantly associated with post-NAC residual tumor cellularity (p=0.74), ER, PR, and HER2 status were individually associated with this measure of response to NAC (p=0.04, 0.01, and 0.01, respectively). However, none of these associations explained more than 2.5% of the variability in this marker of treatment response. Median non-censored follow-up time was 4.26 years. Accounting for censoring, median survival was 13.65 years (lower 95% confidence limit was 11.79 years). Differential associations with OS were observed for three hormone receptor subtypes (ER: p&amp;lt; 0.001, HER2: p=0.04, and TNBC: p&amp;lt; 0.001) according to residual tumor cellularity, classified by percent residual cellularity categories of complete or almost complete response versus all others. Importantly, although ER negative patients with poor residual cellularity response had worse OS than ER positive patients with good response (Hazard Ratio [HR], 95% Confidence Interval [CI] = 4.74, 2.2-10.2), ER negative patients with good response did not have significantly worse OS than ER positive patients with good response (HR, 95% CI = 1.37, 0.57-3.26). Similar patterns were seen for patients with HER2 negative breast cancer or TNBC. Chemo resistant TNBC patients had higher risks for mortality than if they were not chemo resistant (HR, 95% CI: 2.41, 1.02-5.71). Conclusions: Our data suggest that OS associated with different hormone subtypes differs according to response to NAC. Differential OS according to response to NAC is greatest for patients classified according to ER status influences, with good response eliminating much of the differential mortality risk between ER negative and positive patients. There is a similar difference according to TNBC, although the difference appears to be less complete. Further studies should focus on understanding the chemo resistance of ER negative tumors, and perhaps TNBC, to identify mechanisms that may ultimately drive treatment response and survival. Table 1. Demographic and other characteristics Citation Format: Sangeetha Prabhakaran, V. Shane Pankratz, Christopher McNicoll, Nadja Falk, Jacklyn Nemunaitis, Jain Zhou, Payton Sandoval-Belt. Breast cancer patients with different hormone receptor subtypes receiving neoadjuvant chemotherapy (NAC) experience differential overall survival according to their resistance to NAC [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 P6-01-15.

Abstract P1-05-12: Evaluation of the benefit of the tumor marker cancer antigen 15–3 (CA 15-3) in different subtypes of metastatic breast cancer

Abstract Background: Cancer antigen 15-3 (CA 15-3) is the most commonly used tumor marker in patients with breast cancer (BC). However, the usefulness of CA 15-3 is still controversial and there is lack of evidence for its role in metastatic BC. We performed a retrospective analysis of the value of CA 15-3 for monitoring and diagnosis in subgroups of metastatic BC. Method: This retrospective study included three cohorts of a total of 196 patients with advanced or metastatic BC treated during the years 2015-2020. Patients’ data, such as subtype, hormone receptor status, and CA 15-3 values, were retrieved from a treatment database to find out how well the CA 15-3 levels followed the disease progression or remission over time. An increase or decrease of CA 15-3 less than 10% indicated stable disease and changes larger than 10% indicated progress or response of therapy. The patients were then categorized into one of six groups based on the proportion of correct CA 15-3 values in each patient during the course of the disease. A proportion of correct values of 95% or higher placed the patient in category 5, between 90% and 95% category 4, 75% to 90% were category 3, 50% to 75% category 2 and below 50% category 1. Patients without any elevated CA 15-3 values and with no evidence of association with a trend of CA 15-3 and disease progression were categorized as 0. Patients in categories 3, 4, and 5 were classified with approved CA 15-3 conformity and categories 4 and 5 with excellent conformity. Results: The median number of samples per patient was 27 (range 5-102) and at diagnosis of metastatic disease, 79%, 66% and 60% of patients had elevated CA 15-3 in the luminal, HER2-positive, and TNBC groups, respectively. Overall, 72.4%, 95% confidence intervals (CI) (66.2-78.7) of the patients had an approved conformity of CA 15-3 to monitor the course of the disease. The benefit of CA 15-3 differed significantly between the subtypes, luminal BC had an approved conformity for 94%, 95% CI (88.6-99.1) of the patients, HER2 BC 63%, 95% CI (52.1-73.5) and for TNBC 46% (95% CI 29.9-62.0) of patients. In patients with Luminal A, the conformity was excellent in 84% of patients compared to 60% of patients with Luminal B. Estrogen receptor status (ER) was the single most important factor for the value of CA 15-3, with an approved conformity of 91%, 95% CI (85.6-95.7) of ER-positive patients and 37%, 95% CI (25.3-48.2) of all ER-negative patients. Elevated baseline levels of CA 15-3 in the diagnosis of metastatic BC increased the benefit of the marker to approved levels in 62.5% of the ER-negative patients, but ER-positive patients mostly had approved conformity, despite negative CA 15-3 at baseline. Visceral or bone metastases further improved the utility of CA 15-3 and soft tissue or solitary CNS metastases decreased it. Conclusion: The benefit of serum marker CA 15-3 in monitoring patients with metastatic BC depends mainly on whether the tumor expresses ER or not. ER-positive patients were excellently monitored in most cases and elevated CA 15-3 values at baseline indicated potential utility in ER-negative patients. Citation Format: Henrik Lindman, Ebba Cederqvist Molin, Martin Jernling, Aglia Schiza. Evaluation of the benefit of the tumor marker cancer antigen 15–3 (CA 15-3) in different subtypes of metastatic breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P1-05-12.

Evaluation and comparison of different breast cancer prognosis scores based on gene expression data

BackgroundBreast cancer is one of the three most common cancers worldwide and is the most common malignancy in women. Treatment approaches for breast cancer are diverse and varied. Clinicians must balance risks and benefits when deciding treatments, and models have been developed to support this decision-making. Genomic risk scores (GRSs) may offer greater clinical value than standard clinicopathological models, but there is limited evidence as to whether these models perform better than the current clinical standard of care.MethodsPREDICT and GRSs were adapted using data from the original papers. Univariable Cox proportional hazards models were produced with breast cancer-specific survival (BCSS) as the outcome. Independent predictors of BCSS were used to build multivariable models with PREDICT. Signatures which provided independent prognostic information in multivariable models were incorporated into the PREDICT algorithm and assessed for calibration, discrimination and reclassification.ResultsEndoPredict, MammaPrint and Prosigna demonstrated prognostic power independent of PREDICT in multivariable models for ER-positive patients; no score predicted BCSS in ER-negative patients. Incorporating these models into PREDICT had only a modest impact upon calibration (with absolute improvements of 0.2–0.8%), discrimination (with no statistically significant c-index improvements) and reclassification (with 4–10% of patients being reclassified).ConclusionAddition of GRSs to PREDICT had limited impact on model fit or treatment received. This analysis does not support widespread adoption of current GRSs based on our implementations of commercial products.

Prognosis and effectiveness of chemotherapy for medullary breast carcinoma.

We aimed to determine the prognosis and potential benefit of postoperative chemotherapy according to subtype of medullary breast carcinoma (MedBC), a very rare invasive breast cancer. A cohort of 1518 female patients with unilateral MedBC and 284,544 invasive ductal carcinoma (IDC) cases were enrolled from the Japanese Breast Cancer Registry. Prognosis of MedBC was compared to IDC among patients with estrogen receptor (ER)-negative and HER2-negative subtype (553 exact-matched patients) and ER-positive and HER2-negative subtype (163 MedBC and 489 IDC patients via Cox regression). Disease free-survival (DFS) and overall survival (OS) were compared between propensity score-matched adjuvant chemotherapy users and non-users with ER-negative and HER2-negative MedBC. Among ER-negative and HER2-negative subtype patients, DFS (hazard ratio (HR) 0.45; 95% confidence interval (95% CI), 0.30-0.68; log-rank P < 0.001) and OS (HR 0.51; 95% CI 0.32-0.83; log-rank P = 0.004) were significantly better in MedBC than IDC. Patients treated with postoperative chemotherapy showed better DFS (HR 0.27; 95% CI 0.09-0.80; log-rank P = 0.02) and OS (HR 0.27; 95% CI 0.09-0.80; log-rank P = 0.02) compared to those without. For the ER-positive and HER2-negative subtype, the point estimate for HR for DFS was 0.60 (95% CI 0.24-1.22) while that for OS was 0.98 (95% CI 0.46-1.84) for MedBC. In ER-negative and HER2-negative MedBC, the risk of recurrence and death was significantly lower than that of IDC, about half. Postoperative chemotherapy reduced recurrence and mortality. ER-positive and HER2-negative MedBC may have a lower risk of recurrence compared to IDC.

Impact of Surgical Delay on Tumor Upstaging and Outcomes in Estrogen Receptor–Negative Ductal Carcinoma in Situ Patients

The delay of elective surgeries by the coronavirus 2019 (COVID-19) pandemic prompted concern among surgeons to delay estrogen receptor (ER)-negative ductal carcinoma in situ (DCIS) for fear of missing an ER-negative invasive cancer and compromising survival of patients. Female patients ≥40 years old diagnosed with ER-negative DCIS from 2004 to 2017 were examined from the National Cancer Database. Multivariable logistic regression, adjusting for patient and tumor factors, was used to determine factors associated with tumor upstage. Multivariable Cox proportional hazards modeling was used to determine if surgical delay impacted overall survival of ER-negative DCIS patients that were upstaged to invasive disease. There were 219,731 patients with DCIS of which 24,338 (11.1%) had tumor upstage. Of these patients, 5,675 (16.2%) of ER-negative and 18,663 (10.1%) of ER-positive DCIS patients were upstaged (p ≤ 0.001). From 2004 to 2017, ER-negative DCIS upstage rates increased from 12.9% to 18.9%. Independent factors associated with tumor upstage were younger age (odds ratio [OR] 0.75 [95% CI 0.69 to 0.81]) and Black race (OR 1.34 [95% CI 1.22 to 1.46]). Compared with patients with ≤30 days between biopsy and surgery, patients with a 31- to 60-day interval (OR 1.13 [95% CI 1.05 to 1.20]) and a &gt;60-day interval (OR 1.12 [95% CI 1.02 to 1.23]) had an increased rate of tumor upstage. Among ER-negative DCIS patients whose tumors were upstaged to invasive disease, Cox proportional hazard regression modeling showed no association between the number of days between biopsy and surgery and overall survival. Delays in surgery were associated with higher tumor upstage rates but not with worse overall survival.