Hormone Receptor-positive Breast Cancer Patients Research Articles

Abstract P4-09-03: Survival differences between HER2-zero and HER2-low-expressing breast cancer—A meta-analysis of early breast cancer patient data from 12 studies including 39831 patients

Abstract Background: HER2-low-expressing breast cancer takes up 40-50% in all breast cancer subtypes. Survival difference between HER2 low expression and HER2-zero breast cancer remains controversial. Therefore, the aim of this study was to compare the survival outcome of the two subtypes and to explore the impact of hormone receptor status. Methods:A comprehensive medical literature search was performed by PubMed, EMBASE, and the Cochrane Library through June 2022. We included observational studies reporting hazard ratios (HRs) with corresponding 95% confidence intervals (CIs). The results of individual studies were pooled by fixed-effects models. Twelve articles with a total of 39,831 breast cancer patients were included in the meta-analysis. Results:We observed a statistically significant association between low HER2 expression levels and better breast cancer survival outcomes (OS: HR: 0.82; 95% confidence interval: 0.77, 0.88; DFS/RFS: HR: 0.88; 95% confidence interval: 0.83, 0.93). In a subgroup analysis, we found that HER2-low patients had better survival outcomes among hormone receptor-positive breast cancer patients (OS: HR: 0.85; 95% confidence interval: 0.78, 0.92; DFS/RFS: HR: 0.90; 95% confidence interval: 0.84, 0.96). Similarly, in triple-negative breast cancer patients, we also observed a positive association between HER2 low expression and better survival (OS: HR: 0.78; 95% confidence interval: 0.69, 0.87; DFS/RFS: HR: 0.86; 95% confidence interval: 0.77, 0.94). Conclusions: Our study showed that HER2 low expressing breast cancer had better survival outcomes compared to HER2 negative breast cancer in patients with early stage breast cancer, regardless of hormone receptor status. The result has a positive effect on us to further explore the clinical features, molecular characteristics and better treatment strategies of HER2-low-expressing breast cancer. Forest plot of HER2 low expression and overall survival in overall population Forest plot of HER2 low expression and disease free survival or relapse free survival in overall population Citation Format: Xiaoqi Zhang, Ciqiu Yang, Kun Wang. Survival differences between HER2-zero and HER2-low-expressing breast cancer—A meta-analysis of early breast cancer patient data from 12 studies including 39831 patients [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 P4-09-03.

Abstract P5-09-05: A phase II, single-arm study of histone deacetylases inhibitor Tucidinostat and Exemestane as neoadjuvant therapy in patients with hormone receptor positive HER2 negative breast cancer (NeoTEE trial)

Abstract Background: Tucidinostat (formerly known as chidamide) plus exemestane is approved for postmenopausal patients with advanced, hormone receptor-positive breast cancer. We evaluated the efficacy and safety of tucidinostat plus exemestane as the neoadjuvant strategy in hormone receptor-positive early breast cancer patients. Methods: NeoTEE is an open-label, single-center, phase II study. Patients with HR-positive, HER2-negative and stage II/III breast cancer were enrolled at the First Affiliated Hospital of Sun Yat-sen University. Eligible patients received 25 mg oral exemestane once daily for 2 weeks followed by 30 mg oral tucidinostat twice weekly in combination with 25mg oral exemestane once daily for 24 weeks. GnRHa was used for premenopausal patients. Endpoints assessed here included objective response rate (ORR), complete cell cycle arrest (CCCA, Ki-67≤2.7%) at surgery, disease control rate (DCR), pathological complete remission (pCR) and safety. Results: Between July 2020 and July 2022, 26 patients were enrolled, of whom 24 were evaluable for response per RECIST 1.1 criteria. Partial response (PR) was observed in 18 patients, with an ORR of 75% (18/24). The DCR was 100%. Of the 14 patients with surgery, one patient achieved pCR and 8 patients were exempt from postoperative adjuvant chemotherapy. CCCA at surgery was 64.3% (9/14). The follow-up remains ongoing and updated results will be presented thereafter. Most adverse events (AEs) were grade 1 or 2. Grade 3 AEs occurred in 8 of 26 patients, the most common were neutropenia 19.2%, leukopenia 7.7%, anemia 3.8%, ALT increased 3.8%, pneumonitis 3.8%. Only 1 patient experienced grade 4 neutropenia. Grade 3/4 neutropenia recovered after dose reduction or discontinuation of tucidinostat. No patient received G-CSF. Conclusions: Tucidinostat combined with exemestane was well tolerated and demonstrated meaningful responses in neoadjuvant setting for women with early HR+/HER2- breast cancer. Further investigation is warranted. Clinical trial information: NCT04465097. Citation Format: zhen shan, nan shao, xiaoling zhang, huijuan shi, yanling zheng, jia luo, tiantian zhen, ruping chen, Ying Lin. A phase II, single-arm study of histone deacetylases inhibitor Tucidinostat and Exemestane as neoadjuvant therapy in patients with hormone receptor positive HER2 negative breast cancer (NeoTEE trial) [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 P5-09-05.

Abstract P2-03-05: HOXB13/IL17RB-low breast cancers are predicted to respond to PIK3CA inhibitors independent of PIK3CA mutational status

Abstract Background: The Breast Cancer Index is a gene expression-based signature comprising two functional biomarker panels, the Molecular Grade Index (MGI) and the two-gene ratio, HOXB13/IL17BR (H/I). MGI measures tumor proliferation, while H/I measures estrogen signaling. Integration of MGI and H/I provides a single score that quantifies the risk distant recurrence, while H/I alone predicts benefit from extended endocrine therapy (EET). In multiple EET trials, we have shown that hormone receptor-positive (HR+) breast cancer (BC) patients with H/I-high biomarker expression benefit from EET, while those with H/I-low expression do not benefit from such therapy. Previous protein-protein interaction (PPI) dysregulation (dysreg) analysis of H/I-low BC tumors with drug-response-associated dysreg in BC cell lines revealed a significant correlation with response to two PIK3CA inhibitors, suggesting that PIK3CA pathway may represent an exploitable therapeutic vulnerability for H/I-low BC patients. However, given that PIK3CA is frequently mutated in ER+ tumors, the PPI dysreg analysis may merely reflect enrichment of PIK3CA genomic alterations within the H/I-Low BCs. Thus, to determine if a genetic abnormality within the H/I-low BCs accounts for the correlation with PIK3CA inhibitor drug response in BC cell lines, we performed targeted DNA sequencing of H/I-high and H/I-low BC tumors. Methods: DNA was extracted from 44 H/I-high and 30-H/I-low BC samples using a Qiaqen DNeasy Blood & Tissue Kit. Samples were then prepared using the Archer VariantPlex kits according to a modified protocol and sequenced in batches on the Illumina NextSeq platform. To determine if a genetic abnormality within H/I-low BCs accounts for the PPI dysreg correlation with PIK3CA drug response, the magnitude of the sample’s drug associated PPI dysregs was compared to its mutational status. Geneset enrichment (GSEA) functional profiles between BC tissue PPI dysregs and BC cell line drug response-associated PPI dysregs, identified two PIK3CA inhibitors as potential therapeutic drugs for H/I-low tumors. For each PIK3CA drug, the set of leading-edge genes associated with the genesets important to the observed correlation were isolated. Z-score transformed PPI dysreg count data across the BC samples was used to calculate the average dysreg scores for each sample based on the drug-associated leading-edge genes. The samples were sorted based on scores associated with each drug and GSEA was run on each ranked list looking for an association between the dysreg magnitude and PIK3CA mutation status. Results: Targeted DNA sequencing identified copy number variants for in H/I-high and low tumors, the most common of which are: ERBB2 (3/44 H/I-high; 1/30 H/I-low; p: 0.642), FGF19 (3/44 H/I-high; 1/30; p: 0.642), CCND1 (3/44 H/I-high; 1/30 H/I-low; p: 0.642). Sequencing identified a similar distribution of single nucleotide variants (SNVs) between the H/I-high and H/I-low groups. The most common SNVs identified in order of prevalence are PIK3CA (18/44, H/I-high; 6/30, H/I-low; p: 0.078), TP53 (12/44 H/I-high; 6/30 H/I-low; p: 0.585), CDH1 (4/44 H/I-high; 5/30 H/I-low; p: 0.471), BRCA2 (4/44 H/I-high; 2/30 H/I-low; p: 1). No significant difference in mutational prevalence was identified between the H/I-high and H/I-low BCs. No-significant associations between the PPI dysreg magnitude of the drug-associated leading-edge genes and PIK3CA mutational status was observed (AZD6482 FDR=0.736 and A66 FDR=0.95). Conclusion: No significant genetic alteration, including PIK3CA mutational status, was identified between H/I-high and H/I-low groups. Thus, protein-protein interaction (PPI) dysregulation analysis identifies H/I-low BC tumors as those that are predicted to response to PIK3CA inhibitors independent of PIK3CA mutational status. Citation Format: Baris Boyraz, Grace Kirkpatrick, Stefan T. Kaluziak, Robert Morris, Johannes Kreuzer, Wilhelm Haas, Anthony John Iafrate, Dennis Sgroi. HOXB13/IL17RB-low breast cancers are predicted to respond to PIK3CA inhibitors independent of PIK3CA mutational status [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-03-05.

Abstract HER2-06: HER2-06 Outcome analysis of HER2-zero or HER2-low hormone receptor-positive (HR+) breast cancer patients - characterization of the molecular phenotype in combination with molecular subtyping

Abstract Background: Breast cancer with low HER2 expression (HER2-low) is of high clinical relevance because of new therapeutic options with antibody-drug conjugates. We have recently shown in a large cohort from neoadjuvant clinical trials that HER2-low breast cancer has different molecular characteristics as well as different clinical outcomes compared to HER2-zero. Considering the positive correlation between HER2-low expression and hormone receptor positivity observed consistently in many investigations, we have extended our analysis to HR+ tumors from the post-neoadjuvant PenelopeB trial. In PenelopeB, patients with HR+ breast cancer and residual disease after neoadjuvant chemotherapy (NACT) were randomized to post-neoadjuvant palbociclib versus placebo in addition to endocrine therapy. We evaluated the molecular phenotype and clinical outcomes of HER2-low compared to HER2-zero patients. Methods: A total of 1250 patients were randomized, HER2 status was available for 1151 tumors from pretherapeutic core biopsy, determined mainly by local pathology, and from 1213 tumors from the post-NACT sample, determined as part of central pathology. For 1119 patients a paired HER2-status was both available. HER2-zero was defined as IHC0 and HER2-low-positive was defined as IHC1+ or IHC2+/ISH-. Gene expression analysis of 2549 genes using the HTG oncology biomarker panel was performed in 620 pretherapeutic biopsies and 780 post-NACT residual tumor samples, with 539 paired gene expression samples. Breast cancer subtypes were determined using the AIMS approach. Results: In pretherapeutic biopsies, 695 tumors (60%) were HER2-low and 457 (40%) were HER2-zero. A HER2-low status in the biopsy was significantly linked to improved iDFS (HR 0.76 (0.60-0.96; p=0.02). In residual tumors, 632 tumors (60%) were HER2-low and 581 (40%) were HER2-zero, without any prognostic impact of HER2 low status. In addition, a shift of HER2-low-status comparing core biopsy and residual tumor was observed in 415 (37%) of 1119 tumors. 161 (14%) had a shift from HER2-zero to HER2-low and 254 (23%) shifted from HER2-low to HER2-zero. A shift from HER2-zero to HER2-low in the post-NACT samples was significantly linked to reduced iDFS (HR 1.43 [95%CI 1.01-2.01]), p=0.04), compared to HER2-low group, while a shift from HER2-low to HER2-zero was associated with better iDFS compared to HER2-zero group, although not statistically significant (p=0.17). We did not observe a significant correlation of HER2-low status and AIMS molecular subtypes. In particular, the HER2-enriched (HER2E) subtype was assigned to only 4.3% of HER2-zero and 3.1% of HER2-low tumors. Significant iDFS differences were observed for HER2-low-status in combination with AIMS subtypes (lumB/basal/HER2E vs. lumA/normL; overall p-value < 0.0001) for both pretherapeutic biopsies and residual tumor. Patients with post-NACT HER2-low tumors had an improved survival in the subgroups of aggressive AIMS subtypes (lumB/basal/HER2E), but not in the less aggressive AIMs subtypes (lumA/normL), with a positive test for interaction (p=0.02). For the pre-NACT samples a similar, but non-significant trend was observed. We evaluated a total of 620 core biopsies for differences in gene expression comparing HER2-low and HER2-zero tumors. A total of 417 genes were statistically significantly different, but in a hierarchical clustering there was no clear separation of HER2-low and HER2-zero tumors. Conclusions: In the PenelopeB cohort of HR+ tumors, a HER2-low status in pretherapeutic core biopsies is related to improved disease-free survival, especially for those tumors that have a more aggressive intrinsic subtype. A shift of HER2-low status was observed before and after chemotherapy, indicating an adaptation of the pathway activity to therapy-induced stress, which might become relevant for future diagnostic and therapeutic approaches. Citation Format: Carsten Denkert, Miguel Martín, Michael Untch, Hervé R. Bonnefoi, Erik S. Knudsen, Seock-Ah Im, Angela DeMichele, Agnieszka Witkiewicz, Laura Van ’t Veer, Sung-Bae Kim, Harry D. Bear, Nicole McCarthy, Karen Gelmon, Frederik Marmé, José Ángel García-Sáenz, Nicholas Turner, Federico Rojo, Martin Filipits, Lesley-Ann Martin, Peter A. Fasching, Christian Schem, Catherine M. Kelly, Toralf Reimer, Masakazu Toi, Hope Rugo, Michael Gnant, Andreas Makris, Yuan Liu, Karsten Weber, Sivaramakrishna Rachakonda, Sibylle Loibl. HER2-06 Outcome analysis of HER2-zero or HER2-low hormone receptor-positive (HR+) breast cancer patients - characterization of the molecular phenotype in combination with molecular subtyping [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 HER2-06.

E3 Ubiquitin Ligase NEDD4 Affects Estrogen Receptor α Expression and the Prognosis of Patients with Hormone Receptor-Positive Breast Cancer.

Neural precursor cell-expressed developmentally downregulated 4-1 (NEDD4) is an E3 ligase that leads to the degradation of proteins, including estrogen receptor α. We evaluated whether the expression level of NEDD4 affected the outcome of breast cancer patients. We performed a retrospective cohort study enrolling 143 patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative early breast cancer. Of the 66 patients with high NEDD4 mRNA levels (high NEDD4 group) and 77 patients with low NEDD4 mRNA levels (low NEDD4 group), 98.4% and 96.1%, respectively, of the patients had received neoadjuvant/adjuvant hormone therapy. Disease-free survival and overall survival were significantly longer in the low NEDD4 group than in the high NEDD4 group (p = 0.048 and p = 0.022, respectively). Western blotting revealed a high expression of estrogen receptor α in the NEDD4-knockdown culture cells. The proliferation of NEDD4-knockdown cells treated with tamoxifen or estradiol deprivation was suppressed, compared with that of NEDD4-expressing cells. Knockdown of NEDD4 in breast cancer cells induced the accumulation of estrogen receptor α and increased sensitivity to hormone therapy. In summary, this mechanism may lead to a better prognosis in hormone receptor-positive breast cancer patients with a low expression of NEDD4.

The effect of using adjuvant aromatase inhibitors on cognitive functions in postmenopausal women with hormone receptor-positive breast cancer.

Breast cancer is the most frequently diagnosed cancer in women worldwide. Aromatase inhibitors (AIs) are effective treatment options for both early-stage and advanced hormone receptor-positive breast cancer. Because of AIs are used long term in adjuvant therapy, side effects are also very important. It is considered that AIs may affect cognitive functions by decreasing the level of estrogen in the brain. The purpose of our study is that evaluate the relationship between duration of treatment and cognitive functions in patients with breast cancer who use AIs in adjuvant therapy. Two-hundred patients diagnosed with breast cancer who were treated with AIs as adjuvant treatment were included. The patients were surveyed for demographic characteristics. Montreal Cognitive Assessment (MoCA) and Standardized Mini-Mental State Examination (SMMT) tests were performed to evaluate patients' cognitive functions. The total scores of the tests and the orientation, short-time memory, visuospatial functions, attention, language, executive functions which are the MoCA subscales were evaluated separately. Patients were grouped as 0-6, 6-12, 12-24, 24-36, 36, and more months according to the duration of AIs using time. The total MoCA and SMMT scores were affected by factors such as age, education level, and employment status. There was no relationship between duration of treatment and cognitive functions in patients with breast cancer who use AIs in adjuvant therapy (P > 0.05). In addition, no statistically relationship was found in the evaluation of MoCA subscales (P > 0.05). Prolonged adjuvant treatment with AIs does not affect cognitive functions in hormone receptor-positive breast cancer patients.

Peripheral blood lymphocytes predict clinical outcomes in hormone receptor-positive HER2-negative advanced breast cancer patients treated with CDK4/6 inhibitors.

Cyclin-Dependent Kinase 4/6 inhibitors (CDK4/6i) combined with Endocrine Therapy (ET) are the standard treatment for patients with Hormone Receptor-positive/HER2-negative advanced breast cancer (HR+/HER2- aBC). While CDK4/6i are known to reduce several peripheral blood cells, such as neutrophils, lymphocytes and platelets, the impact of these modulations on clinical outcomes is unknown. A multicenter, retrospective-prospective Italian study. We investigated the association between baseline peripheral blood cells, or their early modifications (i.e. 2 weeks after treatment initiation), and the progression-free survival (PFS) of HR+/HER2- aBC patients treated with ETs plus CDK4/6i. Random Forest models were used to select covariates associated with patient PFS among a large list of patient- and tumor-related variables. We evaluated 638 HR+/HER2- aBC patients treated with ET plus CDK4/6i at six Italian Institutions between January 2017 and May 2021. High baseline lymphocyte counts were independently associated with longer PFS [median PFS (mPFS) 20.1 versus 13.2 months in high versus low lymphocyte patients, respectively; adjusted Hazard Ratio (aHR): 0.78; 95% confidence interval (CI): 0.66-0.92; p = 0.0144]. Moreover, patients experiencing a lower early reduction of lymphocyte counts had significantly longer PFS when compared to patients undergoing higher lymphocyte decrease (mPFS 18.1 versus 14.5 months; aHR: 0.82; 95% CI: 0.73-0.93; p = 0.0037). Patients with high baseline lymphocytes and undergoing a lower reduction, or even an increase, of lymphocyte counts during CDK4/6i therapy experienced the longest PFS, while patients with lower baseline lymphocytes and undergoing a higher decrease of lymphocytes had the lowest PFS (mPFS 21.4 versus 11 months, respectively). Baseline and on-treatment modifications of peripheral blood lymphocytes have independent prognostic value in HR+/HER2- aBC patients. This study supports the implementation of clinical strategies to boost antitumor immunity in patients with HR+/HER2- aBC treated with ETs plus CDK4/6i.

Predicting Axillary Response in Hormone Receptor-Positive Breast Cancer after Neoadjuvant Chemotherapy Using Real-World Data.

To develop a scoring system for hormone receptor-positive (HR+) breast cancer patients who are expected to achieve axillary pathological complete response (pCR) after neoadjuvant chemotherapy (NAC). To confirm the correlation between axillary status and survival rate in HR+ breast cancer after NAC. Women from the Shanghai Jiao Tong University Breast Cancer Database (SJTU-BCDB) who underwent NAC for cT1-4N1-3M0 primary HR+ breast cancer between 2009 and 2018 were included in the study. In this case, patient follow up was performed until 2022 for those with complete data before and after NAC. The main outcome measures were the axillary pCR rate, overall survival (OS), and disease-free survival (DFS). The patients were randomly assigned to a test set (n = 175) and a validation set (n = 68) in a 7 : 3 ratio. A prediction risk score was then developed based on the odds ratios from the multivariate analysis of the test set (n = 175) before being validated in the validation set (n = 68). Finally, the Kaplan-Meier curves were used to explore the survival on this score system. From the database, 243 women were included, and the median follow-up period was 47.5 months (95% confidence interval: 41.9-53.1). The axillary pCR rate was 18.9% (46 of 243), with the independent predictors of residual positive axillary lymph nodes (LNs) being lymphovascular invasion (LVI), breast conserving surgery (BCS), Ki67 < 14%, HER2 negativity, positive lymph nodes in ultrasound (US) before surgery, and stage III histological grade (All, P < 0.05). Using the above predictors of the model, the receiver operating characteristic (ROC) curve was used for calibration and inspection, with values for the test and validation sets being 0.847 (P < 0.001; 95% CI: 0.769, 0.925) and 0.813 (P < 0.001; 95% CI: 0.741, 0.885), respectively. The total risk score ranged from 0 to 6 for the multivariate analysis, and from this range, a risk score of 0-2 was defined as a low-risk group, while scores of 3-6 were defined as the high-risk one. By constructing the survival curve, it was found that the 5-year OS rates for the low-risk and high-risk groups were 89.0% and 84.2% (P = 0.236). Similarly, the 5-year DFS rates for the low-risk and high-risk groups were 80% and 68.5% (P = 0.048), respectively. In addition, axillary pathological stages were significantly correlated with the overall survival (OS) and disease-free survival (DFS) (All, P < 0.05). The prediction model showed good performance for HR + breast cancer. LVI, BCS, low Ki-67, HER2 negativity, suspected positive LNs before surgery, and stage III histological grade were all risk factors for residual positive axillary LNs. However, unlike pathological stages, achieving pCR in the axillary LNs does not affect the survival status.

Comparing Genetic Risk and Clinical Risk Classification in Luminal-like Breast Cancer Patients Using a 23-Gene Classifier.

A 23-gene classifier has been developed based on gene expression profiles of Taiwanese luminal-like breast cancer. We aim to stratify risk of relapse and identify patients who may benefit from adjuvant chemotherapy based on genetic model among distinct clinical risk groups. There were 248 luminal (hormone receptor-positive and human epidermal growth factor receptor II-negative) breast cancer patients with 23-gene classifier results. Using the modified Adjuvant! Online definition, clinical high/low-risk groups were tabulated with the genetic model. The primary endpoint was a recurrence-free interval (RFI) at 5 years. There was a significant difference between the high/low-risk groups defined by the 23-gene classifier for the 5-year prognosis of recurrence (16 recurrences in high-risk and 3 recurrences in low-risk; log-rank test: p &lt; 0.0001). Among the clinically high-risk group, the 5-year RFI of high risk defined by the 23-gene classifier was significantly higher than that of the low-risk group (15 recurrences in high-risk and 2 recurrences in low-risk; log-rank test: p &lt; 0.0001). This study showed that 23-gene classifier can be used to stratify clinically high-risk patients into distinct survival patterns based on genomic risks and displays the potentiality to guide adjuvant chemotherapy. The 23-gene classifier can provide a better estimation of breast cancer prognosis which can help physicians make a better treatment decision.

PP095 Clinical significance of 21-gene expression assay in young luminal B type hormone receptor-positive breast cancer patients following surgery

PP095 Clinical significance of 21-gene expression assay in young luminal B type hormone receptor-positive breast cancer patients following surgery

Adherence to endocrine therapy in patients with hormone receptor-positive early-stage breast cancer: a retrospective study.

The persistence and adherence to endocrine therapy (ET) in hormone receptor-positive (HR +) breast cancer patients remain far less than optimal. This retrospective study aimed to evaluate adherence to ET and to identify influencing factors in early-stage HR + breast cancer patients. A stratified random sampling method was used to select patients admitted for breast cancer surgery at a university hospital in Shanghai, China. Patients who received ET medications in the hospital information system (HIS) were included. The primary outcomes were early discontinuation of and adherence to ET. Potential factors influencing the discontinuation and adherence were assessed using univariate and multivariate logistic regression analyses. In total, 706 patients were included, and 161 (22.8%) discontinued ET in less than five years from the first prescription. The discontinuation rates from the one-year to the five-year treatment were 5.38, 16.70, 32.27, 51.52, and 50.00%, respectively (P < 0.001). The rates of adherence (defined as medication possession ratio ≥ 80%) from the first to the fifth year were 85.18, 82.25, 82.18, 72.92, and 73.68%, respectively (P = 0.18). Age, insurance, and surgery type impacted ET discontinuation and adherence. However, the type of medication only impacted the adherence to ET. Persistence and adherence to ET in patients with breast cancer remain far from optimal and decrease over time. More attention should be paid to patients aged ≥ 70years and those without insurance who tend to have early discontinuation of ET.

Establishment and validation of a multigene model to predict the risk of relapse in hormone receptor-positive early-stage Chinese breast cancer patients.

Breast cancer patients who are positive for hormone receptor typically exhibit a favorable prognosis. It is controversial whether chemotherapy is necessary for them after surgery. Our study aimed to establish a multigene model to predict the relapse of hormone receptor-positive early-stage Chinese breast cancer after surgery and direct individualized application of chemotherapy in breast cancer patients after surgery. In this study, differentially expressed genes (DEGs) were identified between relapse and nonrelapse breast cancer groups based on RNA sequencing. Gene set enrichment analysis (GSEA) was performed to identify potential relapse-relevant pathways. CIBERSORT and Microenvironment Cell Populations-counter algorithms were used to analyze immune infiltration. The least absolute shrinkage and selection operator (LASSO) regression, log-rank tests, and multiple Cox regression were performed to identify prognostic signatures. A predictive model was developed and validated based on Kaplan-Meier analysis, receiver operating characteristic curve (ROC). A total of 234 out of 487 patients were enrolled in this study, and 1588 DEGs were identified between the relapse and nonrelapse groups. GSEA results showed that immune-related pathways were enriched in the nonrelapse group, whereas cell cycle- and metabolism-relevant pathways were enriched in the relapse group. A predictive model was developed using three genes ( CKMT1B , SMR3B , and OR11M1P ) generated from the LASSO regression. The model stratified breast cancer patients into high- and low-risk subgroups with significantly different prognostic statuses, and our model was independent of other clinical factors. Time-dependent ROC showed high predictive performance of the model. A multigene model was established from RNA-sequencing data to direct risk classification and predict relapse of hormone receptor-positive breast cancer in Chinese patients. Utilization of the model could provide individualized evaluation of chemotherapy after surgery for breast cancer patients.

4MO Prognostic implication of 21-gene expression assay in luminal B type hormone receptor-positive breast cancer patients younger than 40 years

Recurrence score (RS) based on 21-gene expression assay is widely used to evaluate prognosis and potential benefits of adjuvant chemotherapy (AC) for hormone-receptor positive (HR+) breast cancer (BC) patients (pts). In this study, we investigated clinical significance of RS in premenopausal HR+ BC pts.

Discovery of Highly Functionalized 5-hydroxy-2H-pyrrol-2-ones That Exhibit Antiestrogenic Effects in Breast and Endometrial Cancer Cells and Potentiate the Antitumoral Effect of Tamoxifen.

Tamoxifen improves the overall survival rate in hormone receptor-positive breast cancer patients. However, despite the fact that it exerts antagonistic effects on the ERα, it can act as a partial agonist, resulting in tumor growth in estrogen-sensitive tissues. In this study, highly functionalized 5-hydroxy-2H-pyrrol-2-ones were synthesized and evaluated by using ERα- and phenotype-based screening assays. Compounds 32 and 35 inhibited 17β-estradiol (E2)-stimulated ERα-mediated transcription of the luciferase reporter gene in breast cancer cells without inhibition of the transcriptional activity mediated by androgen or glucocorticoid receptors. Compound 32 regulated E2-stimulated ERα-mediated transcription by partial antagonism, whereas compound 35 caused rapid and non-competitive inhibition. Monitoring of 2D and 3D cell growth confirmed potent antitumoral effects of both compounds on ER-positive breast cancer cells. Furthermore, compounds 32 and 35 caused apoptosis and blocked the cell cycle of ER-positive breast cancer cells in the sub-G1 and G0/G1 phases. Interestingly, compound 35 suppressed the functional activity of ERα in the uterus, as demonstrated by the inhibition of E2-stimulated transcription of estrogen and progesterone receptors and alkaline phosphatase enzymatic activity. Compound 35 showed a relatively low binding affinity with ERα. However, its antiestrogenic effect was associated with an increased polyubiquitination and a reduced protein expression of ERα. Clinically relevant, a possible combinatory therapy with compound 35 may enhance the antitumoral efficacy of 4-hydroxy-tamoxifen in ER-positive breast cancer cells. In silico ADME predictions indicated that these compounds exhibit good drug-likeness, which, together with their potential antitumoral effects and their lack of estrogenic activity, offers a pharmacological opportunity to deepen the study of ER-positive breast cancer treatment.

Real world outcomes with alpelisib in metastatic hormone receptor-positive breast cancer patients: A single institution experience.

It is critically important to study the real-world data of FDA-approved medications to understand the response rates and toxicities observed in the real-world population not represented in the clinical trials. We reviewed charts of patients diagnosed with metastatic, hormone receptor-positive, human epidermal growth factor receptor 2 negative, PIK3CA-mutated breast cancer treated with alpelisib from May 2019 to January 2022. Clinical characteristics and treatment outcomes were collected. The association of clinical characteristics with responses and adverse events (AEs) was evaluated using the logistic regression model. 27 patients were included. Median age at alpelisib initiation 67 years (range: 44, 77 years). Majority of patients had excellent performance status at time of alpelisib initiation. Most patients had chronic comorbidities, notably; 2 patients had controlled type 2 diabetes mellitus at time of alpelisib initiation. Majority had a median of three lines of therapy (range: 1, 7) before alpelisib. Clinical responses were determined using RECIST v1.1. 3/27 (11.11%) patients discontinued therapy before response assessment due to grade 3 AEs. Overall response rate was 12.5% (3/24), with all partial responses (PR). The median duration of response was 5.77 months (range: 5.54, 8.98). 14/27 (51.9%) of patients required dose interruption/reduction. Overall, 23/27 (85.19%) patients discontinued alpelisib of which 11 (47.83%) discontinued alpelisib due to AEs. Median duration of treatment was 2 months in patients who had grade 3 AEs (range: <1.00, 8.30) and 6.28 (1.15, 10.43) in those who did not. Any grade AEs were reported in 24/27 (88.9%) patients, namely, hyperglycemia 16/27 (59.3%), nausea 11/27 (40.7%), diarrhea 10/27 (37.0%), fatigue 7/27 (25.9%) and rash 6/27 (22.2%). Grade 3 AEs were reported in 13/27 patients (50%), namely, hyperglycemia in 7/27 (53.8%) patients followed by skin rash 4/27 (30.8%), GI side effects 3/27 (23.1%). Those with progressive disease as best response to alpelisib, had more non-metabolic comorbidities, higher number of liver metastases, PIK3CA E545K mutations, and shorter duration on therapy compared to those with PR and stable disease. Patients should be counseled about the toxicity and modest benefit observed with alpelisib in real-world clinical practice when used in later lines of therapy.

144P Development of a 6-color multiplex crystal digital PCR assay for the simultaneous detection of ESR1 and PIK3CA mutations in the plasma of metastatic breast cancer patients

Blood-based liquid biopsies have become a real asset for patient treatment management in the field of precision oncology over the past few years, has it allows quick and easy access to tumor genetic alterations of interest. Indeed, circulating tumor DNA (ctDNA) analysis is particularly well suited for longitudinal monitoring with the advantage of covering the potential genetic heterogeneity of metastatic lesions. For Hormone Receptor-positive (HR+) Metastatic Breast Cancer (MBC) patients, mutations on the ESR1 (encoding the estrogen receptor (ER) alpha), and PIK3CA (encoding the phosphatidylinositol-3-kinase (PI3K) catalytic subunit p110-alpha) genes are emerging clinical biomarkers that can both guide clinicians in their choice of treatment.

Full Compliance of Adjuvant Endocrine Therapy Is Associated with Higher Disease-Free Survival in Hormone Receptor-Positive and HER2-Negative Chinese Breast Cancer Patients with First Tumor Recurrence

To characterize the compliance status of adjuvant endocrine therapy (aET) and its relationship with disease-free survival (DFS) in hormone receptor-positive (HR+) and HER2-negative (HER2-) in Chinese breast cancer (BC) patients with first tumor recurrence. All women with primary unilateral stage I - III HR+HER2- BC and first tumor recurrence in 2008 - 2018 at our institution were identified. Full (vs. none/partial) compliance of aET was classified from records. Multivariate Cox regression estimated the hazard ratio (HR), its 95% confidence interval (CI), and p value. DFS. Covariates included age, T stage, N stage, pathology, tumor grade, LVI, chemotherapy, radiotherapy. Results: A total 258 patients had average age 47.4 years at BC diagnosis and median DFS 31.7 months. Patients with ipsilateral (contralateral) region and organ recurrence were 47.7% (19.8%) and 71.9%. Compared to the patients with none/partial compliance of aET, the full compliance patients (54.3% ) had a higher DFS (median 35.0 vs. 25.2 months, p=0.009). Multivariate analysis showed that the full compliance of aET was associated with a lower HR 0.614 (95%CI 0.467 - 0.807, p<0.001) on recurrence. Early discontinuation (67.5%, 56/83) due to the drug side effects was the top reason for partial compliance of aET. Full compliance of aET was quite low in Chinese HR+HER2- BC patients. However, it was associated with a 38.6% lower risk of first tumor recurrence. To search for effective tools to improve the compliance of aET in this population should be stressed.

1725P Metastasis-resident bacteria in advanced hormone receptor-positive breast cancer are related to primary tumor microbiota and show distinct composition

Tumor-resident bacteria are an emerging component of the tumor microenvironment. Recent studies have shown their presence over multiple cancer types. Lately, mechanistic evidence in a murine breast cancer model indicates that these bacteria promote the metastatic process. However, the presence and conformation of the microbiome of human metastatic tumors have not been determined. Here, we characterized tumor-resident bacteria in a cohort of metastatic hormone receptor-positive breast cancer (MHRBC) patients with matched primary tumors. We performed bacterial 16S rDNA sequencing targeting hypervariable regions V2-4 and V6-9 on FFPE tissues from 40 patients with MHRBC and their matched primary tumors. Sequence data were processed using high resolution sample inference with DADA2. Controls included normal breast tissue, paraffin from all blocks and a simulated bacterial community, comprising known intra and extracellular bacteria. Taxonomy was assigned using the SILVA database v138. Feature selection was used to determine amplicon sequences in primary tumors related to their metastasis. A machine learning classifier was generated to predict the metastatic site from selected amplicons. α-diversity was similar among sample types, while β-diversity showed segregation between metastatic and primary tumors. Alphaproteobacteria, Gammaproteobacteria and Bacilli had increased relative abundance across metastatic and primary tumors. Differential abundance of Proteobacteria and Firmicutes species was identified in metastatic tumors. A machine learning classifier using the 5 top ranked amplicons in primary tumors was capable of 100% precision and high recall for prediction of bone and liver metastatic site, but not lung metastases. We identified and categorized the tumor-resident bacteria of MHRBC. To our knowledge, this is the first study looking at the composition of metastatic breast cancer microbiome. While insights have been gained on primary tumor microbiota, the role of metastasis-resident bacteria including local immunity and treatment resistance warrants further study.

Acupuncture for hot flashes in hormone receptor-positive breast cancer, a coordinated multinational study: Rationale and design of the study protocol

BackgroundAcupuncture has been reported to reduce hot flashes in patients with breast cancer undergoing adjuvant hormonal therapy. Although hot flashes are common, the prevalence varies among cultures, races, and ethnicities; the efficacy of acupuncture across cultures has not been investigated. MethodsThis is a coordinated multinational study, including three parallel randomized trials with a planned analysis of individual patient data, to test the effectiveness of acupuncture on hot flash-related symptoms in hormone receptor-positive breast cancer patients on adjuvant endocrine therapy. Using a standardized acupuncture protocol (total across all three studies of n = 80) versus usual care (total n = 80), symptoms are assessed using changes in the Endocrine Symptom Subscale of Functional Assessment of Cancer Therapy-Endocrine Symptoms. Secondary outcomes include hot flash severity, quality of life, and sleep quality. Differences in response to acupuncture between participants in the three countries will also be explored. DiscussionHere we describe the design of a protocol for a coordinated multinational study, with attention to the complex considerations in developing a multinational research effort testing a non-pharmacologic intervention. This protocol and approach provide guidance for future efforts to evaluate and test non-pharmacologic interventions across multinational populations. Trial registrationclinicaltrials.gov (Identifier: NCT00797732, registered on December 21, 2018), Chinese Clinical Trial Registry (ChiCTR2100045888), and The Clinical Research Information Service (CRIS) of Korea (Registration number: KCT0003618).

Palbociclib Induces the Apoptosis of Lung Squamous Cell Carcinoma Cells via RB-Independent STAT3 Phosphorylation.

Lung squamous cell carcinoma (LUSC) treatment response is poor and treatment alternatives are limited. Palbociclib, a cyclin-dependent kinase (CDK) 4/6 inhibitor, has recently been approved for hormone receptor-positive breast cancer patients and applied in multiple preclinical models, but its use for LUSC therapy remains elusive. Here, we investigated whether palbociclib induced cell apoptosis and dissected the underlying mechanism in LUSC. We found that palbociclib induced LUSC cell apoptosis through inhibition of Src tyrosine kinase/signal transducers and activators of transcription 3 (STAT3). Interestingly, palbociclib reduced STAT3 signaling in LUSC cells interfered by retinoblastoma tumor-suppressor gene (RB), suggesting that pro-apoptosis effect of palbociclib was independent of classic CDK4/6-RB signaling. Furthermore, palbociclib could suppress IL-1β and IL-6 expression, and therefore blocked Src/STAT3 signaling, which were rescued by either recombinant human IL-1β or IL-6. Moreover, Myc mediated the sensitivity of LUSC cells to palbociclib. Our discoveries demonstrated that palbociclib induces apoptosis of LUSC cells through the Src/STAT3 axis in an RB-independent manner, and provided a reliable experimental basis of clinical studies in LUSC patients.