Positive Human Epidermal Growth Factor Research Articles

Tailoring advanced breast cancer treatment after cyclin-dependent kinase 4/6 inhibitors progression - real-world data analysis.

Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) represent the gold standard of the hormone receptor positive human epidermal growth factor receptor 2 (HER-2) negative advanced breast cancer. However, optimal treatment after disease progression is a matter of debate. We aimed to assess predictive and prognostic factors associated with the treatment outcome following CDK4/6i progression. We retrospectively analyzed patients who progressed on CDK4/6i treatment between 2018 and 2024. Treatment based on molecular findings (PIK3CA mutation), genetic findings (BRCA1/2 germline mutation), or adapted to the change in the tumor phenotype in rebiopsy (anti-HER2 therapy in the transformation to HER-2-positive disease) was grouped into tailored treatment and compared to the endocrine-based therapy and chemotherapy alone. Five hundred twelve patients were treated with CDK4/6i. Two hundred patients with disease progression were enrolled in the study. Duration of response to CDK4/6i was not predictive of the response to subsequent treatment, whereas the progression in the central nervous system was the worst prognostic factor. Thirty patients were ineligible for subsequent treatment. Survival after CDK4/6i progression was significantly longer in patients eligible for tailored treatment. The median PFS in patients with tailored treatment (n=19) was 13.5 months vs. 4.9 months in patients with non-tailored therapy (n=151; p=0.045). 12-month PFS was 54.1% with tailored treatment [95% CI 24.1-76.7%] compared to 18.5% with non-tailored therapy [95% CI 11.6-26.6%]. The median OS for patients treated with a tailored approach was not reached compared to 11.5 months with non-tailored treatment (p=0.016). The 24-month OS for patients treated with a tailored approach was 80.2% [95% CI 40.3-94.8%] compared to 21.1% [95% CI 12.2-31.7%] for patients with non-tailored treatment. Tailoring of subsequent treatment strategy seems to be essential for achieving long-term benefit. Further studies are required, as the prognosis after CDK4/6i progression remains dismal, especially in cases affecting the central nervous system.

Prognostic and Predictive Significance of HER2-low Expression in Metastatic Hormone Receptor Positive Breast Cancer Patients Receiving CDK4-6 Inhibitor Therapy

Objective: This study aimed to analyze the predictive and prognostic value of HER2-low expression in hormone receptor (HR) positive human epidermal growth factor receptor-2 (HER2) negative metastatic breast cancer patients receiving cyclin-dependent kinase-4/6 inhibitor (CDK4/6i) therapy. Methods: This retrospective study included patients who received CDK4/6i plus endocrine therapy (ET). The pathological and clinical characteristics and survival times of the patients were compared and analyzed. Results: Our study included 122 patients. There were HER2-zero 88(72%) and HER2-low 34 (28%) patients. The median progression free survival (mPFS) of all patients who received CDK4/6i+ET was 21 (95% confidence interval (CI),18.5–23.5) months, while mPFS was not reached in the HER2-zero group, and mPFS in the HER2-low group was 12 (95%CI, 6.8–17.1) months (p=0.001). The mPFS was shorter in patients with primary endocrine resistance (6 vs. 21 months, p=0.001). There was a change in the HER2-low status of 26(45%) patients with recurrence compared to the first biopsy. In the HER2-zero and HER2-low groups, 22(25%) and 24(71%) patients, respectively, progressed with CDK4/6i+ET (p=0.001). Estrogen receptor (ER) levels less than and greater than 50% resulted different mPFS (6 and 21 months, respectively) (p=0.025). Median PFS differed based on CDK4/6i+ET combination, treatment line, and best treatment response (all p=0.001). In multivariate analysis, HER2 status(p=0.018), chemotherapy status(p=0.006), best response status with CDK4/6i (p=0.001) for PFS, and best response status with CDK4/6i therapy (p=0.007) for OS were significant. Conclusions: In patients with HR+HER- metastatic breast cancer receiving CDK4/6i therapy, the duration of mPFS was lower in the HER2-low group than that in the HER2-zero group. HER2-low expression is a predictive biomarker of response to CDK4/6 inhibitor therapy.

The prognostic value of preoperative neoindices consisting of lymphocytes, neutrophils and albumin (LANR) in operable breast cancer: a retrospective study.

Preoperative inflammatory factors and nutritional status are strongly associated with the prognosis of a variety of cancers. We explored the relationship between preoperative lymphocytes, neutrophils and albumin (LANR) and progression-free survival in breast cancer patients. The clinical and follow-up data of 200 breast cancer patients were retrospectively analyzed in this study, and the value of LANR was determined as follows: LANR, lymphocytes × albumin/neutrophils. ROC curves, COX proportional risk regression analysis and subgroup analysis were used to assess the prognostic value of LANR in progression-free survival of breast cancer patients. The median age of the patients was 55.5 years (range 50-62 years). The median follow-up time was 46 months (range 33-55 months). In progression-free survival, the area under the LANR curve was 0.748 and the HR (95% CI) was 0.035 (0.679-0.817). LANR was associated with age (p=0.02), positive axillary lymph nodes (p<0.001), TNM stage (p<0.001) and human epidermal growth factor receptor 2(p=0.004). The results indicated that preoperative LANR may be a reliable predictor of progression-free survival in patients with operable breast cancer. LANR may be an essential predictor for breast cancer patients and provides a therapeutic basis for clinicians and patients.

Overexpressing S100A9 ameliorates NK cell dysfunction in estrogen receptor-positive breast cancer

BackgroundEstrogen receptor (ER) positive human epidermal growth factor receptor 2 (HER2) negative breast cancer (ER+/HER2−BC) and triple-negative breast cancer (TNBC) are two distinct breast cancer molecular subtypes, especially in tumor immune microenvironment (TIME). The TIME of TNBC is considered to be more inflammatory than that of ER+/HER2−BC. Natural killer (NK) cells are innate lymphocytes that play an important role of tumor eradication in TME. However, studies focusing on the different cell states of NK cells in breast cancer subtypes are still inadequate.MethodsIn this study, single-cell mRNA sequencing (scRNA-seq) and bulk mRNA sequencing data from ER+/HER2−BC and TNBC were analyzed. Key regulator of NK cell suppression in ER+/HER2−BC, S100A9, was quantified by qPCR and ELISA in MCF-7, T47D, MDA-MB-468 and MDA-MB-231 cell lines. The prognosis predictability of S100A9 and NK activation markers was evaluated by Kaplan–Meier analyses using TCGA-BRAC data. The phenotype changes of NK cells in ER+/HER2−BC after overexpressing S100A9 in cancer cells were evaluated by the production levels of IFN-gamma, perforin and granzyme B and cytotoxicity assay.ResultsBy analyzing scRNA-seq data, we found that multiple genes involved in cellular stress response were upregulated in ER+/HER2−BC compared with TNBC. Moreover, TLR regulation pathway was significantly enriched using differentially expressed genes (DEGs) from comparing the transcriptome data of ER+/HER2−BC and TNBC cancer cells, and NK cell infiltration high/low groups. Among the DEGs, S100A9 was identified as a key regulator. Patients with higher expression levels of S100A9 and NK cell activation markers had better overall survival. Furthermore, we proved that overexpression of S100A9 in ER+/HER2-cells could improve cocultured NK cell function.ConclusionIn conclusion, the study we presented demonstrated that NK cells in ER+/HER2−BC were hypofunctional, and S100A9 was an important regulator of NK cell function in ER+BC. Our work contributes to elucidate the regulatory networks between cancer cells and NK cells and may provide theoretical basis for novel drug development.

Abstract PO3-05-11: Enhancing the interpretation of real-world quality of life (QoL) in patients (pts) with hormone receptor positive human epidermal growth factor 2 negative (HR+/HER2−) advanced breast cancer (ABC) enrolled in the POLARIS trial

Abstract Background POLARIS is a prospective, observational real-world study of pts with HR+/HER2− ABC receiving palbociclib in routine clinical practice. We have previously shown that palbociclib treatment did not have any significant adverse impact on pt QoL when assessed by the EORTC-QLQ-C30 questionnaire,1 consistent with published clinical trial findings. Now, to enhance interpretation, we sought to characterize EORTC scores (using updated POLARIS data) into terms that are meaningful to pts, physicians, and other stakeholders, using a similar approach to established clinical problem threshold methodology.2 Methods EORTC data were collected at baseline (BL), monthly for the first 3 months, and every 3 months thereafter until palbociclib discontinuation. Response options for each EORTC question (ordinal scale from 1=very poor to 7=excellent) were grouped into “favorable” (taking a conservative approach of using only responses 5, 6 or 7) and “less favorable” (response of ≤4) for the two items on global health status/QoL. The proportion of pts with favorable or less favorable response was compared between subgroups (line of therapy, age, race, bone metastases, visceral metastases, and dose modification) at timepoints BL, month 6, 12, and 18 using Fisher’s exact test. Results Between January 2017 and December 2018, 1285 pts were enrolled, of whom 1250 received at least one dose of palbociclib and subsequently analyzed as part of the final data cut of 09 Jan 2023. EORTC Q29 ‒ Overall Health completion rates were 1167/1250 (93.4%) at baseline, 732/1250 (58.6%) at month 6, 484/1250 (38.7%) at month 12, and 353/1250 (28.2%) at month 18 (Table). The proportion of pts with a favorable response for EORTC Q29 was consistently higher than with a not favorable response (BL, 56.1% vs 43.9%; month 6, 69.3% vs 30.7%; month 12, 68.6% vs 31.4%; and month 18, 70.0% vs 30.0%; Table). When analyzed by subgroup, no significant differences were observed in the proportion of pts with a favorable (to less favorable) response for any subgroup covariate, except for age at BL; however, this significance was not observed at month 6, 12 or 18 (Table). Similar results were observed for EORTC Q30 – Overall QoL (data not shown). Conclusions The proportion of pts indicating a favorable response in the EORTC questionnaire Overall Health and Overall QoL questions increased or were maintained in pts with HR+/HER2− ABC treated with palbociclib from BL through to month 18 across overall and all subgroups. It is important to note that these data are conditional on the pts who responded to the questions, whose numbers diminished over time. XX XX Citation Format: Gabrielle Rocque, Joanne Blum, Yan Ji, Timothy Pluard, John Migas, Shailendra Lakhanpal, Erin Jepsen, Eric Gauthier, Yao Wang, Monica Montelongo, Joseph C. Cappelleri, Connie Chen, Meghan Karuturi, Debu Tripathy. Enhancing the interpretation of real-world quality of life (QoL) in patients (pts) with hormone receptor positive human epidermal growth factor 2 negative (HR+/HER2−) advanced breast cancer (ABC) enrolled in the POLARIS trial [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 PO3-05-11.

Abstract PO1-04-13: CARDIAC-STAR: Prevalence of Cardiovascular Comorbidities in Hormone Receptor Positive Human Epidermal Growth Factor Negative metaStatic breasT cAnceR

Abstract BACKGROUND: Baseline cardiovascular (CV) comorbidities can impact treatment decisions for patients (pts) with metastatic breast cancer (mBC). There is limited data on the prevalence of CV comorbidities at the time of hormone receptor positive human epidermal growth factor negative (HR+/HER2-) mBC diagnosis. The primary objective of this study is to describe the prevalence of pre-existing CV comorbidities in women and men with newly diagnosed HR+/HER2- mBC. A secondary objective is to describe the first documented cancer treatment for patients with or without CV comorbidities. METHODS: Women and men ≥18 years of age with newly diagnosed HR+/HER2- mBC from 01/2016 to 12/2021 were included in this retrospective, observational study using the Merative™ Marketscan® Commercial and Medicare Databases which is nationally representative. Evidence of mBC was defined as having two or more claims containing one or more diagnosis code for BC at least 30 days apart and at least two secondary malignancy diagnosis codes. Previously published claims-based algorithms were used to identify the HR+/HER2- molecular subtype. The index date is defined as the date of first mBC diagnosis. Patients had a 1-year pre-index period for observation of CV comorbidities and a 6-month post-index period for first documented cancer treatmen RESULTS: We identified 5,452 pts with HR+/HER2- mBC, 99% of whom were female, with a median age of 58 years (yrs) (IQR 13), and 83% having a health plan from an employer; i.e., are still employed. At mBC diagnosis, 3,335 pts (61.2%) had at least one pre-existing CV comorbidity (see Table). The most reported CV comorbidities were hypertension (50.7%), hyperlipidemia (33.7%), and diabetes (19.2%). The median age of pts with or without a CV comorbidity was 61 and 52 yrs, respectively; 16.2% with CV comorbidities were ≥75 yrs. Additional data, including first documented treatment, will be presented at the meeting. CONCLUSIONS: The prevalence of CV comorbidities in pts with HR+/HER2- mBC is often underrecognized. In this analysis, more than half of pts had at least one CV comorbidity by mBC diagnosis. CV comorbidities may impact treatment decisions in the HR+/HER2- mBC population, particularly in older pts. Table Citation Format: Susan Dent, Avirup Guha, Heather Moore, Rachael McCaleb, Irene Arias, Stella Stergiopoulos, Benjamin Li, Doris Makari, Michael Fradley. CARDIAC-STAR: Prevalence of Cardiovascular Comorbidities in Hormone Receptor Positive Human Epidermal Growth Factor Negative metaStatic breasT cAnceR [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 PO1-04-13.

Abstract PO4-20-03: HIPEx: Adjuvant palbociclib plus endocrine therapy in ER-positive HER2-negative early breast cancer with high recurrence score according to GenesWellTM BCT; a multi-center single arm phase II clinical trial (KCSG BR 19-13)

Abstract Background: In estrogen receptor (ER)-positive human epidermal growth factor receptor2 (HER2)-negative early breast cancer (EBC) patients, NCCN treatment guideline recommend 21-gene tests for decision of adjuvant chemotherapy if tumor size is over 0.5cm or node positive disease. In addition, GenesWellTM BCT is a prognostic assay that predict the risk of recurrence in patients with ER-positive HER2-negative and nodal stage 0-1 EBC. According to gene tests, EBC patients with high recurrence risk would have help from adjuvant chemotherapy to increase the rate of disease free survival but toxicities of chemotherapy are not negligible. Therefore, the effort for escaping adjuvant chemotherapy has been performed and currently CDK4/6 inhibitor would be considered as the substitute for cytotoxic chemotherapy in ER-positive HER2-negative EBC patients. Methods: HIPEx trial is a multi-center, phase II clinical trial to determine the efficacy of adjuvant palbociclib plus endocrine therapy in ER-positive HER2-negative EBC with high recurrence score according to GenesWellTM BCT (NCT04247633). Eligible patients are women who received curative surgery and diagnosed as ER-positive, HER2-negative and pathologic stage T1b-T2 and/or N0-1. Clinical recurrence risk is high according to the modified Adjuvant! Online guideline and GenesWellTM BCT score is 4 or more which being genomic high risk. Other criteria include ECOG performance status ≤1, adequate organ functions and availability of an archival surgical specimens. Patients receive palbociclib 125mg once daily for 21 days of 28-day cycle plus tamoxifen or aromatase inhibitor (anastrozole, letrozole or exemestane) once daily for every day. Palbociclib would be taken for two years and endocrine therapy for five years or more. If adjuvant radiotherapy is required, palbociclib should be taken two weeks after the end date of radiotherapy. If patients are premenopausal status, GnRH agonist is allowed. Primary endpoint is 3-year event free survival (EFS) rate of high clinical and genetic risk ER-positive EBC. Secondary endpoints include 3-year overall survival, quality of life, safety and tolerability of palbociclib with endocrine therapy as an adjuvant setting, exploratory analysis of predictive and prognostic biomarkers and the performance of GenesWellTM BCT for 3-year EFS rate. In total, 578 patients would be enrolled in this trial. Based on the previous results of GenesWell™ BCT in Korea, the 3-year EFS rate for the past control group (chemotherapy followed by endocrine therapy) is 87.0% and the treatment group in this clinical trial is assumed to be 90.5%.(hazard ratio for EFS = 0.717). Null hypothesis is the 3year-EFS rate in patients received adjuvant palbociclib and endocrine therapy is not less than that of the past control group. Alternative hypothesis is the 3year-EFS rate of this trial is less than that of the past control group (one-sided). Significance level is 0.025, power is 0.80. Considering 10% drop out rate, 4-years of accrual patient enrollment and 3-years of follow up period, 578 patients were required in this clinical trial. Citation Format: Ji-Yeon Kim, Sung Hoon Sim, Jieun Lee, In Hae Park, Kyong Hwa Park, Seock-Ah Im, Jee Hung Kim, Kyoung Eun Lee, Jeong Eon Lee, Jai Min Ryu, Young Kee Shin, Yeon Hee Park. HIPEx: Adjuvant palbociclib plus endocrine therapy in ER-positive HER2-negative early breast cancer with high recurrence score according to GenesWellTM BCT; a multi-center single arm phase II clinical trial (KCSG BR 19-13) [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 PO4-20-03.

Ultrasound deep learning radiomics and clinical machine learning models to predict low nuclear grade, ER, PR, and HER2 receptor status in pure ductal carcinoma in situ.

Low nuclear grade ductal carcinoma in situ (DCIS) patients can adopt proactive management strategies to avoid unnecessary surgical resection. Different personalized treatment modalities may be selected based on the expression status of molecular markers, which is also predictive of different outcomes and risks of recurrence. DCIS ultrasound findings are mostly non mass lesions, making it difficult to determine boundaries. Currently, studies have shown that models based on deep learning radiomics (DLR) have advantages in automatic recognition of tumor contours. Machine learning models based on clinical imaging features can explain the importance of imaging features. The available ultrasound data of 349 patients with pure DCIS confirmed by surgical pathology [54 low nuclear grade, 175 positive estrogen receptor (ER+), 163 positive progesterone receptor (PR+), and 81 positive human epidermal growth factor receptor 2 (HER2+)] were collected. Radiologists extracted ultrasonographic features of DCIS lesions based on the 5th Edition of Breast Imaging Reporting and Data System (BI-RADS). Patient age and BI-RADS characteristics were used to construct clinical machine learning (CML) models. The RadImageNet pretrained network was used for extracting radiomics features and as an input for DLR modeling. For training and validation datasets, 80% and 20% of the data, respectively, were used. Logistic regression (LR), support vector machine (SVM), random forest (RF), and eXtreme Gradient Boosting (XGBoost) algorithms were performed and compared for the final classification modeling. Each task used the area under the receiver operating characteristic curve (AUC) to evaluate the effectiveness of DLR and CML models. In the training dataset, low nuclear grade, ER+, PR+, and HER2+ DCIS lesions accounted for 19.20%, 65.12%, 61.21%, and 30.19%, respectively; the validation set, they consisted of 19.30%, 62.50%, 57.14%, and 30.91%, respectively. In the DLR models we developed, the best AUC values for identifying features were 0.633 for identifying low nuclear grade, completed by the XGBoost Classifier of ResNet50; 0.618 for identifying ER, completed by the RF Classifier of InceptionV3; 0.755 for identifying PR, completed by the XGBoost Classifier of InceptionV3; and 0.713 for identifying HER2, completed by the LR Classifier of ResNet50. The CML models had better performance than DLR in predicting low nuclear grade, ER+, PR+, and HER2+ DCIS lesions. The best AUC values by classification were as follows: for low nuclear grade by RF classification, AUC: 0.719; for ER+ by XGBoost classification, AUC: 0.761; for PR+ by XGBoost classification, AUC: 0.780; and for HER2+ by RF classification, AUC: 0.723. Based on small-scale datasets, our study showed that the DLR models developed using RadImageNet pretrained network and CML models may help predict low nuclear grade, ER+, PR+, and HER2+ DCIS lesions so that patients benefit from hierarchical and personalized treatment.

Consensus on the clinical use of CDK4/6 inhibitors for the treatment of hormone receptor-positive human epidermal growth factor receptor 2-negative breast cancer (2023 edition)

Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors have led transformative breakthrough of clinical therapy for hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER-2)-negative breast cancer patients. CDK4/6 inhibitors that have been marketed in China include Ribociclib, Palbociclib, Abemaciclib and Dalpiciclib. For HR-positive HER-2-negative locally advanced and metastatic breast cancer, CDK4/6 inhibitors combined with endocrine therapy have become standard regimen, which can prolong the survival of patients. In the adjuvant treatment stage of early breast cancer, CDK4/6 inhibitors have also achieved positive results and been approved for indications. At present, CDK4/6 inhibitors have been widely used in clinical practice in China. In order to further improve the standardized application of CDK4/6 inhibitors in China, the Breast Cancer Expert Committee of the National Center for Cancer Quality Control and the Professional Committee of Clinical Research of Cancer Drugs of the Chinese Anti-Cancer Association organized the related expert to update the consensus based on the "CDK4/6 inhibitor consensus on clinical application of in the treatment of hormone receptor positive human epidermal growth factor receptor 2 negative advanced breast cancer (2021 edition)" . The updated consensus systematically introduces the pharmacological characteristics, drug monitoring and adverse event management, etc., of CDK4/6 inhibitors to promote the accuracy of clinical decision-making with the ultimate goal to prolong the overall survival of patients and improve the quality of life.

Elacestrant for ER-Positive HER2-Negative Advanced Breast Cancer.

This article aims to discuss elacestrant, an oral selective estrogen receptor downregulator approved by the Food and Drug Administration (FDA) in January 2023 for the treatment of hormone receptor positive (HR+) human epidermal growth factor receptor 2 negative (HER2-) advanced breast cancer. PubMed, Embase, Medline, Clinicaltrials.gov, and the National Comprehensive Cancer Network (NCCN) were searched from inception to August 31, 2023. Clinical trials published in English were included and relevant information regarding methodology and results were extracted. Phase 1 and 3 trials showed elacestrant was safe and improved progression-free survival in patients with endocrine receptor 1 (ESR1) mutations who failed cyclin-dependent kinase 4/6 inhibitor (CDK 4/6i) plus 1 prior endocrine therapy compared with standard of care (SOC) (fulvestrant, anastrozole, letrozole, or exemestane monotherapy). Elacestrant maintains a comparable adverse event profile with other endocrine therapies and offers an alternative to typical sequential therapy which can delay the use of or be used after traditional chemotherapy. Elacestrant is currently being studied in CDK 4/6 inhibitor naïve patients and as a component of combination therapy for first-line use which could lead to future indications. Elacestrant gained FDA approval in January 2023 and can be considered in patients with HR+ HER2- advanced breast cancer and ESR1 mutations who have progressed despite therapy with either CDK 4/6i plus aromatase inhibitors (AI) or fulvestrant or chemotherapy.

Assessment High-Risk Breast Cancer in Older Patients: A Comparative Analysis of PREDICT Scores and TAILORx Risk Categorization.

This study aimed to evaluate the relationship between PREDICT tool overall survival (OS) scores and high-risk patients according to TAILORx risk categorization in elderly hormone reseptor (HR) positive human epidermal growth factor negative early breast-cancer patients. We conducted a retrospective study, extracting data from medical records of 64 patients diagnosed with breast cancer. A retrospective analysis was performed on all patients who had Oncotype Dx Recurrence Scores across five medical centers between 2017 and 2022. PREDICT scores were defined as calculated 10-year OS rates via PREDICT tool. The median age of the patients was 67, with a range between 65-75 years. Low-risk patients had a slightly higher two PREDICT scores compared to high-risk patients (78% vs. 73%), (81% vs. 77%), which were statistically significant. The progesterone receptor (PR) level was significantly lower in the high-risk group (3.5% vs. 80%). A unit decrease in the PREDICT scores was associated with a 11% increase in the odds of being in the high-risk group. However, these effects weren't statistically significant in the multivariate analysis. A unit decrease in the PR level was significantly associated with increased odds (by 5% in the multivariate analysis) of being in the high-risk group. Our study underscores the importance of using a combination of tools, including the PREDICT tool, PR levels, and TAILORx risk categorization, for a comprehensive risk assessment in these patients, especially in the older population. Accurate risk assessment is crucial for tailoring the treatment and optimizing outcomes in this vulnerable population. Future studies are warranted to further validate these findings in larger cohorts and to explore additional biomarkers and genomic signatures that may aid in the risk assessment and management of breast cancer in older patients.

Stratified endocrine therapy for advanced breast cancer: stratification guided, combination preferred

The endocrine therapy of hormone receptor (HR)-positive human epidermal growth factor receptor 2 (HER2)-negative breast cancer has stepped into an era of targeted combination therapy. Many targeted agents, led by cyclin-dependent kinase 4/6 inhibitor (CDK4/6i), have provided abundant treatment options for patients with HR-positive HER2-negative advanced breast cancer. To meet the needs of clinical practice in China and standardize the administration of targeted agents, the stratified endocrine strategy for advanced breast cancer has been proposed by Chinese Society of Clinical Oncology (CSCO) Breast Cancer guidelines based on medicine evidence and drug accessibility, offering scientific and organized decision-making guidance for clinical oncologists.

Association Between Level of Expression of Human Epidermal Growth Factor Receptor 2 (Her-2 Neu) And Age Among Breast Cancer Patients

Objective: To determine the association between human epidermal growth factor receptor 2 with age among patients presenting with breast cancer. Study Design: Comparative cross-sectional study. Place and Duration of Study: Medical Oncology Department, Jinnah Postgraduate Medical Centre, Karachi Pakistan, from Aug 2019-Jan 2020. Methodology: Total 194 females of age 20-85 years with confirmed diagnosis of breast cancer were included in the study. The immunohistochemistry was done for the status of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 and the validation of human epidermal growth factor receptor 2 was done by Fluorescent In situ Hybridization technique in each female. Results: The patient’s age was from 24-82 years old with mean age of 46.57±11.45 year. Out of 194, 108 cases had positive progesterone receptor expression (55.7%), 114 had positive estrogen receptor expression (58.8%) and 67 had positive human epidermal growth factor receptor 2 expression (34.5%). The females of age greater 46 years were more likely to be human epidermal growth factor receptor 2 positive as compared to females of age less and equal to 46 years. Conclusion: The results showed that females with age more than 40 years have significant association with human epidermal growth factor receptor 2, whereas age is an independent variable with regards to estrogen receptor and progesterone receptor status.

The prognostic significance of skin involvement in breast cancer patients with chest wall recurrence

Purpose To assess the prognostic significance of skin involvement in breast cancer patients with chest wall recurrence (CWR). Methods We retrospectively analyzed the clinicopathological data of breast cancer patients with CWR who were diagnosed pathologically between January 2000 and April 2020. Disease-free survival (DFS) was the time from radical resection for CWR to disease recurrence. Progression-free survival (PFS) was defined as the time from the diagnosis of locally unresectable CWR to the first sign of disease progression. Persistent chest wall progression was defined as three consecutive chest wall progressions with no distant organ involvement. Results A total of 476 patients with CWR were included in this study. Skin involvement was confirmed in 345 patients. Skin involvement was significantly correlated with a high T stage (p = 0.003), more positive nodes at initial examination (p < 0.001) and lymphovascular invasion (p < 0.001). Kaplan–Meier analysis showed that skin involvement was a predictor of shorter DFS (p < 0.001), including both local disease progression (p < 0.001) and distant disease progression (p = 0.022). Multivariate analysis showed that skin involvement was an independent biomarker for DFS (p = 0.043). Patients with skin involvement were more likely to experience persistent chest wall progression (p = 0.040). After eliminating the potential deviation caused by an insufficient follow-up time, persistent chest wall progression was more likely to be associated with a high N stage (p = 0.002), negative progesterone receptor (PR; p = 0.001) and positive human epidermal growth factor receptor 2 (HER2; p = 0.046) of the primary site, and negative oestrogen receptor (ER; p = 0.027) and PR (p = 0.013) of the chest wall lesion and skin involvement (p = 0.020). Conclusion Skin involvement was a predictor of poor disease control in patients with CWR and was closely related to persistent chest wall progression. We stratified the prognosis of individualized treatment for breast cancer patients with CWR to provide new insights into the biological behaviours of the disease.

Efficacy of post‑mastectomy radiotherapy in patients with T1‑2N1 breast cancer aged ≤35years or with a positive HER‑2 status.

Post-mastectomy radiotherapy (PMRT) is highly recommended for patients with breast cancer with one to three positive nodes; however, there remains some controversy regarding its use. The present retrospective study aimed to explore which patients may be able to avoid PMRT and its associated side effects. A total of 728 patients with T1-2N1 breast cancer who were treated with or without PMRT were included in the present study. The results suggested that PMRT significantly decreased the locoregional recurrence rate (LRR) [hazard ratio (HR)=5.602, 95% confidence interval (CI)=3.139-9.998, P<0.01; 3-year LRR: 4 vs. 17%] and improved overall survival (OS) (HR=0.651, 95% CI=0.437-0.971, P=0.03; 3-year OS: 91 vs. 87%) for patients with T1-2N1 breast cancer. By contrast, PMRT had no significant effect on the distant metastasis (DM) rate (HR=0.691, 95% CI=0.468-1.019, P=0.06; 3-year DM: 10 vs. 15%). Further stratified analysis revealed that PMRT did not reduce the LRR and DM, or improve OS in patients aged ≤35 years or in those with a positive human epidermal growth factor receptor-2 (HER-2) status. The analysis of 438 patients treated with PMRT revealed that patients aged ≤35 years or those with a positive HER-2 status were more likely to experience local recurrence even following PMRT. Thus, the benefits of using PMRT in patients with T1-2N1 breast cancer who are aged ≤35 years or in those with a positive HER-2 status need to be carefully considered. Further studies are required to confirm whether this patient group may be exempted from PMRT.

Real-World Outcomes of CDK4/6 Inhibitors Treatment in Metastatic Breast Cancer in Romania.

The introduction in clinical practice of selective cyclin-dependent kinase (CDK) 4/6 inhibitors improves the outcome of patients with hormone receptor (HR)-positive human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (mBC). In Romania, the three available CDK 4/6 inhibitors (Palbociclib, Ribociclib and Ademaciclib) have been approved by the National Agency for Medicines (ANM) in 2019, 2020 and 2021. We conducted a retrospective study from 2019 to 2022 on 107 patients with metastatic breast cancer HR+ that have been treated with CDK 4/6 inhibitors in addition to hormone therapy in the Oncology Department of Colțea Clinical Hospital in Bucharest. The purpose of this study is to calculate the median progression-free survival (PFS) and to compare it with the median PFS from other randomized clinical trials. A key difference from other studies is that our study evaluated both patients with non-visceral mBC and patients with visceral mBC, as these two groups often have different outcomes. A total of 79.4% were postmenopausal patients and 20.6% were premenopausal; 42.1% had different stages at the beginning of disease and 57.9% presented newly metastatic disease. Median PFS was 17 months, unlike randomized clinical trials which reported a median PFS of 25.3 months. The combination of CDK 4/6 inhibitors with endocrine therapy is the golden standard treatment in HR-positive, HER2-negative metastatic breast cancer, bringing a prolongation of survival for these patients. Our results show no major differences compared to randomized clinical trials, despite the smaller patient group. In order to have a picture of the efficacy of the treatment as close as possible to the real-world data, we believe that it would be very useful to have a collaboration between several oncology departments in different institutions to carry out a multi-center study on large groups of patients.

A randomized phase 2 non-inferiority trial of (Z)-endoxifen and exemestane + goserelin as neoadjuvant treatment for premenopausal women with ER+/HER2- breast cancer (EVANGELINE).

TPS633 Background: Ovarian function suppression (OFS) when combined with tamoxifen or an aromatase inhibitor is the standard of care for premenopausal estrogen receptor positive (ER+) human epidermal growth factor receptor 2 negative (HER2-) breast cancer (BC) based on SOFT (Francis 2022) and TEXT (Pagani 2022) clinical trials and confirmed in a metanalysis (EBCTCG 2022). However, estrogen deprivation in premenopausal women is associated with significant morbidity and up to 40% of premenopausal women with ER+/HER2- BC are intolerant of OFS. For these women, tamoxifen monotherapy is the only FDA approved option. Therefore, there is substantial room to improve endocrine therapy for premenopausal women with ER+/HER2- BC. (Z)-endoxifen is one of the most active anti-estrogen tamoxifen metabolites, with preclinical data demonstrating superiority to tamoxifen and letrozole in aromatase expressing xenograft models and evidence for antitumor activity in early phase clinical trials in patients with prior progression on endocrine therapy including tamoxifen. In addition to its ability to potently block ERa, (Z)-endoxifen at clinically achievable concentrations inhibits protein kinase C beta 1 (PKCβ1), resulting in downstream AKT inhibition and apoptosis. It is hypothesized that (Z)-endoxifen, when delivered as monotherapy at doses that dually target both ERα and PKCβ1, will potently inhibit BC proliferation while obviating the need for OFS in premenopausal women. If successful, this innovative approach could spare women with endocrine sensitive BC from the side effects of OFS. Methods: To further study (Z)-endoxifen in premenopausal women, a multicenter study in the United States, with possible expansion to other countries was designed (EVANGELINE; NCT05607004). This is a Phase 2, open-label, randomized, neoadjuvant study in premenopausal women with Stage IIA or IIB ER+/HER2- BC. Subjects are randomized 1:1 to either exemestane plus goserelin or (Z)-endoxifen. The primary objective is to determine whether the endocrine sensitive disease (ESD) rate (defined as Ki-67 ≤ 10% after 4 weeks of neoadjuvant therapy) with (Z)-endoxifen is non-inferior to exemestane plus goserelin. Subjects will be enrolled with the intent of surgical treatment in the involved breast(s) after completing 6 months of neoadjuvant treatment. Safety, tolerability, response rates and surgical outcomes will be assessed. Disease progression will be monitored throughout study participation. Paired tumor biopsies and blood sampling will allow for a robust biomarker evaluation. Prior to initiating the Treatment Cohort (162 subjects), up to 12 subjects will be enrolled in a pharmacokinetic (PK) Run-in Cohort to identify the optimal dose for the Treatment Cohort. Enrolment in the PK Run-in cohort began in February 2023. Clinical trial information: NCT05607004 .

Effect of Concurrent Proton Pump Inhibitors With Palbociclib Tablets for Metastatic Breast Cancer

BackgroundPalbociclib is indicated for the treatment of hormone receptor positive (HR+) human epidermal growth factor receptor 2 negative (HER2-) metastatic breast cancer (MBC) in combination with an aromatase inhibitor or fulvestrant. Two retrospective studies found that concurrent proton pump inhibitor (PPI) use with palbociclib capsules significantly reduced progression free survival (PFS) versus patients without a PPI. Palbociclib tablets were released in 2020 without restriction on PPI use. No study to date has evaluated the combination of palbociclib tablets with concurrent PPI use. MethodsPatients were retrospectively evaluated after they received palbociclib tablets for the treatment of HR+ HER2- MBC in the first line setting with or without a PPI. Patients were assigned to the no PPI use arm if they never used a PPI and the PPI use arm if they used a PPI for >50% of the duration of palbocicib therapy. The primary endpoint was PFS. The secondary endpoints included overall survival (OS) and adverse events. ResultsEighty-two patients were identified; 50 in the no PPI use group and 32 in the PPI use group. The median PFS was 20.6 months (95% confidence interval [CI], 16.07 to not estimable) in the no PPI use arm versus 21.0 months (95% CI, 15.15 to not estimable) in the PPI use arm (P = 0.95). Median OS was not reached in either arm. Adverse effects did not differ between arms. ConclusionUse of a concurrent PPI with palbociclib tablets does not significantly reduce PFS in patients treated for HR+ HER2- MBC.

Optimal treatment strategy for hormone receptor-positive human epidermal growth factor receptor 2-negative breast cancer patients with 1-2 suspicious axillary lymph node metastases on breast magnetic resonance imaging: upfront surgery vs. neoadjuvant chemotherapy.

It is unclear whether upfront surgery or neoadjuvant chemotherapy is appropriate for first treatment in hormone receptor (HR)-positive human epidermal growth factor receptor 2 (HER2)-negative breast cancer patients with 1-2 suspicious axillary lymph node (ALN) metastases on preoperative breast magnetic resonance imaging (MRI). We identified 282 patients with HR+HER2- breast cancer and 1-2 suspicious ALN metastases on baseline breast MRI (147 received upfront surgery; 135 received neoadjuvant chemotherapy). We evaluated the predictive clinicopathological factors for pN2-3 in the adjuvant setting and axillary pathologic complete response (pCR) in the neoadjuvant setting. Lymphovascular invasion (LVI)-positive and clinical tumors >3cm were significantly associated with pN2-3 in patients who received upfront surgery. The pN2-3 rate was 9.3% in patients with a clinical tumor ≤ 3cm and LVI-negative versus 34.7% in the others (p < 0.001). The pN2-3 rate in patients with a clinical tumor ≤ 3cm and LVI-negative and in the others were 9.3% versus 34.7% in all patients (p < 0.001), 10.7% versus 40.0% (p = 0.033) in patients aged < 50 years, and 8.5% versus 31.0% in patients aged ≥ 50 years (p < 0.001), respectively. In the neoadjuvant setting, patients with tumor-infiltrating lymphocytes (TILs) ≥ 20% had a higher axillary pCR than those with TILs < 20% (46.7% vs. 15.3%, p < 0.001). A similar significant finding was also observed in patients < 50 years. Upfront surgery may be preferable for patients aged ≥ 50 years with a clinical tumor < 3cm and LVI-negative, while neoadjuvant chemotherapy may be preferable for those aged < 50 years with TILs ≥ 20%.

PRECYCLE: multicenter, randomized phase IV intergroup trial to evaluate the impact of eHealth-based patient-reported outcome (PRO) assessment on quality of life in patients with hormone receptor positive, HER2 negative locally advanced or metastatic breast cancer treated with palbociclib and an aromatase inhibitor or palbociclib and fulvestrant

BackgroundEfficacy and quality of life (QoL) are key criteria for therapy selection in metastatic breast cancer (MBC). In hormone receptor positive (HR +) human epidermal growth factor receptor 2 negative (HER2 −) MBC, addition of targeted oral agents such as everolimus or a cycline-dependent kinase 4/6 (CDK 4/6) inhibitor (e.g., palbociclib, ribociclib, abemaciclib) to endocrine therapy substantially prolongs progression-free survival and in the case of a CDK 4/6i also overall survival. However, the prerequisite is adherence to therapy over the entire course of treatment. However, particularly with new oral drugs, adherence presents a challenge to disease management. In this context, factors influencing adherence include maintaining patients’ satisfaction and early detection/management of side effects. New strategies for continuous support of oncological patients are needed. An eHealth-based platform can help to support therapy management and physician–patient interaction.MethodsPreCycle is a multicenter, randomized, phase IV trial in HR + HER2 − MBC. All patients (n = 960) receive the CDK 4/6 inhibitor palbociclib either in first (62.5%) or later line (37.5%) together with endocrine therapy (AI, fulvestrant) according to national guidelines. PreCycle evaluates and compares the time to deterioration (TTD) of QoL in patients supported by eHealth systems with substantially different functionality: CANKADO active vs. inform. CANKADO active is the fully functional CANKADO-based eHealth treatment support system. CANKADO inform is a CANKADO-based eHealth service with a personal login, documentation of daily drug intake, but no further functions. To evaluate QoL, the FACT-B questionnaire is completed at every visit. As little is known about relationships between behavior (e.g., adherence), genetic background, and drug efficacy, the trial includes both patient-reported outcome and biomarker screening for discovery of forecast models for adherence, symptoms, QoL, progression free survival (PFS), and overall survival (OS).DiscussionThe primary objective of PreCycle is to test the hypothesis of superiority for time to deterioration (TTD) in terms of DQoL = “Deterioration of quality of life” (FACT-G scale) in patients supported by an eHealth therapy management system (CANKADO active) versus in patients merely receiving eHealth-based information (CANKADO inform).EudraCT Number: 2016–004191-22