Positive Breast Cancer Research Articles

Interaction between Estrogen Receptors and p53: A Broader Role for Tamoxifen?

Tamoxifen is one of the most widely used anticancer drugs in the world. It is a safe drug with generally well-tolerated side effects and has been prescribed for the treatment of early-stage and advanced-stage or metastatic estrogen receptor alpha (ERα/ESR1) -positive breast cancer. Tamoxifen therapy also provides 38% reduction of the risk of developing breast cancer in women at high risk. With the advent of newer medications targeting ERα-positive breast cancer, tamoxifen is now mainly used as adjuvant therapy for lower-risk premenopausal breast cancer and cancer prevention. It is widely accepted that tamoxifen as a selective estrogen receptor modulator (SERM) exerts its therapeutic effect by competitively binding to ERα leading to recruitment of co-repressors and inhibition of transcription of genes involved in the proliferation of breast cancer epithelium. As such, expression of ERα in breast tumors has been considered necessary for tumors to be responsive to tamoxifen therapy. However, ERα-independent effects of tamoxifen in various in vitro and in vivo contexts have been reported over the years. Importantly, recent discovery that ERα and estrogen receptor beta (ERβ/ESR2) can bind tumor suppressor protein p53 with functional consequences has provided new insights into the mechanisms underlying response to tamoxifen therapy and resistance. Furthermore, these findings have paved the way for broadening the use of tamoxifen by potentially repurposing it to treat triple negative (negative for ERα, human epidermal growth factor receptor 2/HER2, and progesterone receptor/PR) breast cancer (TNBC). Herein, we summarize these developments and discuss their mechanistic underpinnings and clinical implications.

Tumor-infiltrating lymphocytes in HER2-positive breast cancer: potential impact and challenges.

In this review, we evaluate the role of stromal tumor-infiltrating lymphocytes (sTILs) as a biomarker in human epidermal growth factor receptor 2 (HER2)-positive breast cancer, exploring the prognostic and predictive potential in various treatment settings. Data from multiple clinical trials in the early and metastatic settings, focusing on TILs' correlation with pathologic complete response (pCR), progression-free survival (PFS), and overall survival across early and metastatic HER2-positive breast cancer were summarized. This review also discusses TILs' assessment methods, interobserver variability, and emerging technologies to assess TILs. TILs have been identified as a highly reproducible biomarker that predicts pCR in patients receiving neoadjuvant therapy and serves as a prognostic indicator for long-term outcomes in several breast cancer subtypes, including HER2-positive. Studies indicate that higher TIL levels correlate with better recurrence-free survival rates. Despite these findings, there is no consensus on the optimal TIL threshold for clinical decision making, and further research is required on how to incorporate TILs into routine clinical practice. TILs represent a promising biomarker in HER2-positive breast cancer, particularly in early disease settings. This assessment could guide treatment de-escalation or intensification, tailoring therapies to individual patient profiles. Due to their prognostic importance, TILs can be added to pathology reports. However, further validation in clinical trials is essential for the widespread adoption of TILs in clinical practice.

Implementation of model-informed precision dosing for tamoxifen therapy in patients with breast cancer: A prospective intervention study.

Tamoxifen is an estrogen-receptor (ER) antagonist, used as adjuvant treatment of ER-positive breast cancer. It is converted by CYP2D6 into endoxifen, its most active metabolite. Patients with endoxifen plasma concentrations <16nM face a higher risk of recurrence. The use of a priori model-informed precision dosing (MIPD) may lead to faster target attainment and thus potentially improve patient outcomes. In total, 106 evaluable patients were prospectively included in this single-arm MIPD-intervention study. Patients received a model-predicted tamoxifen dose when starting tamoxifen-treatment (65.1% of patients received 20mg, 16.0% received 30mg and 18.9% received 40mg). Seventy-five percent of the 40mg group was predicted to be unable to reach the threshold of 16nM despite receiving the highest registered dose. After attaining steady-state, 84.0% of patients reached endoxifen levels ≥16nM, which was not significantly higher compared to a historical control cohort (77.9%, p=0.17). The model showed adequate performance and correctly identified patients requiring 40mg tamoxifen. Endoxifen samples that were acquired 4-6 weeks after treatment initiation, are informative of steady-state endoxifen levels and can be used to inform MIPD and adjust tamoxifen dosing prior to steady-state attainment. In this first MIPD implementation study for patients treated with tamoxifen, MIPD did lead to more patients achieving endoxifen levels ≥16nM as compared to the one-dose-fits-all strategy, albeit insignificant. This may partly be explained by a larger proportion of patients who were recommended to switch to an aromatase inhibitor (AI) in the intervention cohort. In conclusion, MIPD seems beneficial compared to one-size-fits-all-dosing, but TDM still remains an important addition.

Antibody-drug conjugates targeting SSEA-4 inhibits growth and migration of SSEA-4 positive breast cancer cells.

Although breast cancer treatment has evolved significantly in recent years, drug resistance remains a major challenge. To identify new targets for breast cancer, we found that stage-specific embryonic antigen 4 (SSEA-4) is expressed in all subtypes of breast cancer cell lines, and the increased expression of the associated enzymes β3GalT5 and ST3Gal2 correlates with poor recurrence-free survival (RFS) in breast cancer. We also found that SSEA-4 antibodies can be rapidly internalized into breast cancer cells, a property that makes SSEA-4 an attractive target for antibody-drug conjugates (ADCs). Furthermore, the SSEA-4 antibody conjugated to the anticancer agents showed efficacy against SSEA-4-positive breast cancer cells, including those resistant to PARP inhibitor, trastuzumab, and CDK7 inhibitor. In addition, SSEA-4 ADCs showed no efficacy in β3GalT5-knockout MDA-MB-231cells, highlighting the essential role of SSEA-4 as the target antigen for ADCs activity. Our work shows that SSEA-4-ADCs could be a therapeutic option for breast cancers.

HER2DX in HER2-positive inflammatory breast cancer: correlative insights and comparative analysis with noninflammatory breast cancers.

The HER2DX assay predicts long-term prognosis and pathologic complete response (pCR) in patients with early-stage human epidermal growth factor receptor 2 (HER2)-positive breast cancer receiving neoadjuvant systemic therapy but has not been evaluated in inflammatory breast cancer (IBC). HER2DX was analyzed in baseline biopsy tissues from 23 patients with stage III HER2-positive IBC on a phase II trial (NCT01796197) treated with neoadjuvant trastuzumab, pertuzumab, and paclitaxel (THP). To assess the assay's predictive accuracy for pCR in IBC, clinical-pathological features and outcomes from this IBC cohort were compared with 156 patients with stage III HER2-positive non-IBC from four different cohorts. Comparative analyses included HER2DX scores, gene signatures, and expression of individual genes between patients with IBC and non-IBC. Notable differences in clinicopathological characteristics included higher pertuzumab and chemotherapy usage and lower axillary burden in patients with IBC compared with non-IBC. In the combined cohort (n= 179), HER2DX pCR score and pertuzumab use were significant predictors of pCR, but not IBC status. The pCR rates in patients treated with trastuzumab-based chemotherapy (including IBC and non-IBC) were 68.9%, 58.5%, and 16.3% in the HER2DX pCR-high, -medium, and -low groups, respectively. Comparative gene expression analysis indicated minor differences between IBC and non-IBC affecting individual HER2, immune, and proliferation genes. The HER2DX pCR score could predict pCR in stage III HER2-positive IBC following treatment with de-escalated neoadjuvant systemic therapy and in stage III HER2-positive non-IBC. Elevated pCR rates in HER2-positive IBC with high HER2DX pCR scores suggest there may be a role for treatment de-escalation in these patients and confirmatory studies are justified.

Discovery of a sushi domain-containing protein 2-positive phenotype in circulating tumor cells of metastatic breast cancer patients

Cell lines derived from circulating tumor cells (CTCs) in the blood provide important biological information on cancer metastasis. CTC-ITB-01 is a CTC cell line derived from a patient with metastatic estrogen receptor-alpha (ER-alpha) positive breast cancer two months before the death of the patient. After a LC-MC/MS based proteomics analysis of CTC-ITB-01, we found extraordinary high levels of the poorly characterized protein SUSD2 (sushi domain-containing protein 2) in CTC-ITB-01. Expression of SUSD2 on subsets of CTCs was validated on clinical blood samples of patients with metastatic breast cancer. SUSD2-positive CTCs could be captured specifically by a MACS-based approach. We overexpressed SUSD2 in the poorly-metastatic cell line MCF-7. This resulted in upregulation of ER-alpha, the tumor progression protein GRP78 (78-kDa glucose-regulated protein) and downregulation of the tumor suppressor protein PDCD4 (programmed cell death protein 4). We observed downregulation of SUSD2 and PDCD4 after hypoxia and simulation of re-oxygenation in the blood in MCF-7 and MDA-MB-468, while in CTC-ITB-01 SUSD2 levels remained unchanged, and only PDCD4 was downregulated under hypoxia. In conclusion, we show, for the first time, that SUSD2 is expressed in CTCs and appears to affect key proteins in tumor progression and survival.

Epigenetic Therapy in Hormone Positive Breast Cancer: The Role of PIK3CA

Epigenetic Therapy in Hormone Positive Breast Cancer: The Role of PIK3CA

Outcomes and treatment patterns for stage I human epidermal growth factor receptor 2-positive breast cancer in the Surveillance, Epidemiology, and End Results database, 2010-2019.

The risk of recurrence in patients with small, lymph node-negative, human epidermal growth factor receptor 2 (HER2)-positive breast cancers untreated with adjuvant chemotherapy/HER2-directed therapy is uncertain. To investigate this, the authors conducted a retrospective, population-based study of chemotherapy use and breast cancer-specific survival (BCSS) among patients with stage IA HER2-positive breast cancer. The authors analyzed Surveillance, Epidemiology, and End Results data from patients diagnosed with stage IA HER2-positive breast cancer from 2010 to 2019. They examined the frequency of chemotherapy use by tumor size and hormone receptor (HR) status and applied multivariate logistic regression to assess the factors associated with receipt of chemotherapy. BCSS was evaluated and performed multivariable Cox regression was performed to evaluate the association between chemotherapy receipt and BCSS. Among 12,896 patients, 74.0% had HR-positive/HER2-positive breast cancer, and 26.0% had HR-negative/HER2-positive breast cancer. Adjuvant chemotherapy was received by to 58.9% of patients, with lower utilization for those who were older, Hispanic or Asian/Pacific Islander, separated/divorced/widowed, or had a lower median household income. The median follow-up was 46 months. Among the patients who had pathologic T1 (pT1) microscopic, pT1a, or pT1b tumors, the 5-year BCSS rate was 97.6%-99.6% in those who had no evidence of chemotherapy receipt in the medical record versus 98.4%-100.0% in those who did receive chemotherapy. Among patients who had pT1c tumors and had no evidence of chemotherapy receipt, the 5-year BCSS rate was 92.1% for those with HR-negative/HER2-positive breast cancer and 96.0% for those with HR-positive/HER2-positive breast cancer. Patients who had pT1c tumors and received chemotherapy had a 5-year BCSS rate of 96.7% in those with HR-negative/HER2-positive breast cancer and 98.7% in those with HR-positive/HER2-positive breast cancer. In this large, population-based study of patients with stage IA HER2-positive breast cancer, patients who had tumors ≤1 cm had excellent outcomes with or without chemotherapy. Patients with pT1c tumors had a greater increase in BCSS with the receipt chemotherapy.

Ongoing Symptoms and Concerns Experienced by Low-Risk Breast Cancer Survivors Following Active Treatment.

Little is known about the symptom burden of breast cancer survivors with early-stage disease. Many studies have focused on symptoms of patients who are undergoing or recently completed systemic therapy. However, with the increased use of Oncotype DX, the proportion of early-stage hormone receptor-positive patients who undergo chemotherapy has declined, making existing studies of the symptom experience less useful for these patients. The aim of this study was to assess symptom burden for early-stage breast cancer survivors. Eligible survivors had stage I-II, estrogen receptor (ER)- or progesterone receptor (PR)-positive and HER2neu-negative breast cancer, did not receive chemotherapy, were 6 months-5 years post-diagnosis, and were cancer-free. Survivors were enrolled at the University of Wisconsin Breast Center follow-up visits and were emailed a link to a patient-reported outcomes (PRO) survey. Survey domains were informed by American Cancer Society/American Society of Clinical Oncology (ACS/ASCO) survivorship guidelines and survivor/provider stakeholders. The prevalence of clinically significant symptoms are reported. Overall, 98 patients participated. On average, participants were 61.3 years of age (standard deviation [SD] 11.5) and 2.5 years post-diagnosis (SD 1.2); 71.3% underwent breast-conserving surgery. The average item-level missingness rate was low (2.0%). Most survivors (86.2%) experienced symptoms (38.8% reporting one to two symptoms; 47.9% reporting more than three symptoms). Early-stage breast cancer survivors report a high symptom burden. Given nearly 50% of survivors report more than three symptoms, many topics may not be discussed or addressed during time-limited follow-up visits. Some symptoms, such as sexual health, may be less feasible to address in-clinic given their complex/sensitive nature. Use of PROs allows for a comprehensive evaluation and identification of unrecognized needs, representing an opportunity to improve survivorship care.

Performance of sentinel lymph node biopsy after neoadjuvant chemotherapy in clinically node positive breast cancer patients: systematic review and meta-analysis.

The reliability of sentinel lymph node biopsy (SLNB) after neoadjuvant chemotherapy (NACT) in patients with initially node-positive breast cancer is still controversial. This meta-analysis is conducted to investigate the feasibility and accuracy of SLNB after NACT in patients with initially positive axillary nodes. We conducted a literature search using Medline, PubMed, Embase, Central, and SCOPUS up until April 2021 for studies on the performance of SLNB following NACT. We included prospective studies including breast cancer patients with positive lymph nodes at diagnosis and received NACT before undergoing SLNB irrespective of their molecular subtypes or stage. Our main outcomes of interest were the identification rate (IR) and the false negative rate (FNR) of SLNB. We included an aggregate of 33 studies in this meta-analysis enrolling 4,624 patients. The reported IR ranged from a minimum of 77.6% to a maximum of 100% and resulted in a pooled IR of 88% (95%CI: 86-90, I2:80.9%). The FNR reported in the studies ranged from a minimum of 5.1% to a maximum of 43% and showed a pooled FNR of 13% (95% CI: 11-15, I2: 72.31%). The subgroup analysis demonstrated that the usage of dual mapping technique could decrease the FNR and increase the IR. Moreover, the number of lymph nodes retrieved inversely correlated with FNR (p<0.01). Our findings support the feasibility and accuracy of SLNB after NACT in initially node-positive breast cancer patients, that converted to clinically node negative when performed in properly selected cases. SLNB offers a less invasive approach in selected patients sparing them the morbidity associated with ALND. This approach aligns with efforts to de-escalate surgical management in breast cancer and reinforces that SLNB post-NACT should be incorporated into clinical practice, provided that stringent patient selection and procedural standards are maintained.

Imapct of radiation and trastuzumab therapy on echocardiographic parameters in her2 positive breast cancer patients- eight years follow-up

Abstract Background Trastuzumab has benefits in treatment of HER2 positive breast cancer. However its also carries the risk of cardiotoxicity and in addition of prior radiotherapy, the risk is higher. Purpose To assess the imapct of radiation and trastuzumab therapy on echocardiographic parameters at the end of completing treatment period, as well as during follow up period of eight years in HER2 positive breast cancer patients(pts). Methods At the beginning, the study included a group of 96 HER2 positive breast cancer patients(mean age, 59.57±9.6 years). During 8 years follow up after last cycle of trastuzumab, 6 pts died and connection was lost with 68 pts. Eight-year follow-up was conducted on 22 pts. All pts uderwent trastuzumab therapy and 11 pts had radiation before trastuzumab. In all pts echocardiography study was performed before and after trastuzumab and 8 years after the last cycle of trastuzumab. Results In all 22 pts after trastuzumab therapy ejection fraction(EF) decreased(from64.63±7.047% to 63.28±4.74%, p= 0.238 ), while left atrium (LA) (from 33.54±5.00 mm to 34.09±3.86 mm, p=0.384) and left ventricular mass (LVM) (from162.43±46.40 g to 172.36±48.04 g, p=0.434) increased but not significantly. After 8 year follow up period value of EF was lower by 4,91%, LVM was higer by 11,71% and dimension of right ventricle (RV) was significantly higer by 26,74% (p&amp;lt;0,004) in the subgroup of pts with radiation therapy and trastuzumab(N=11) then in subgroup of pts with only trastuzumab therapy. Conclusions The results of the study showed decrease of LVEF and increase of LVM and LA after trastuzumab therapy. During 8 years follow up, pts with radiation and trastuzumab had greater reduction of EF and increase of LVM and RV than those with trastuzumab therapy without radiation.

CXCR4 promotes tumor stemness maintenance and CDK4/6 inhibitors resistance in ER-positive breast cancer

BackgroundCDK4/6 inhibitors have significantly improved the survival of patients with HR-positive/HER2-negative breast cancer, becoming a first-line treatment option. However, the development of resistance to these inhibitors is inevitable. To address this challenge, novel strategies are required to overcome resistance, necessitating a deeper understanding of its mechanisms. Recent research has identified several dysregulated genes in CDK4/6 inhibitors-resistant breast cancer, but the underlying mechanism is complex due to tumor heterogeneity and warrants further investigation.MethodsRNA sequencing and KEGG pathway analysis was carried out to identify the mainly dysregulated genes in CDK4/6 inhibitors-resistant breast cancer cells. The effects of CXCR4 knockdown and overexpression via siRNAs and plasmids transfection were examined by mammosphere formation, RT-qPCR, flow cytometry, MTT and colony formation assays. The regulation mechanisms were analyzed by RT-qPCR, western blotting and immunofluorescence experiments. Mouse xenografts were used to analyze the role of CXCR4 in regulation palbociclib sensitivity in vivo. Additionally, we collected the clinical samples and performed immunohistochemistry to analyze the clinical significance of CXCR4.ResultsIn our study, we focused on cancer stem cells, a critical contributor to cancer metastasis and therapy resistance, and detected an upregulation of stemness in our established palbociclib-resistant ER-positive breast cancer cells. Additionally, our research pinpointed CXCR4 as a pivotal gene responsible for maintaining cancer stemness and promoting palbociclib resistance. Mechanistically, CXCR4 activates the WNT5A/β-catenin signaling pathway by enhancing the expression of WNT5A and β-catenin, facilitating the nuclear translocation of β-catenin protein. Targeting CXCR4 using siRNAs or small molecular inhibitors effectively reduces cancer stemness and reverses palbociclib resistance both in vitro and in vivo. Clinical sample analysis further underscores the overactivation of the CXCR4/WNT5A/β-catenin axis in palbociclib-resistant breast cancer, suggesting CXCR4 as a potential biomarker for predicting resistance to CDK4/6 inhibitors.ConclusionsCollectively, our study demonstrates that CXCR4 overexpression plays a vital role in maintaining breast cancer stemness and promoting resistance to CDK4/6 inhibitors through the activation of the WNT5A/β-catenin pathway. Targeting CXCR4 may offer a promising therapeutic approach for advanced CDK4/6 inhibitor-resistant ER-positive breast cancer.

SGK3 promotes estrogen receptor-positive breast cancer proliferation by activating STAT3/ZMIZ2 pathway to stabilise β-catenin.

Breast cancer is a leading threat to women's health, with approximately 70% of cases being estrogen receptor-positive. SGK3 is regulated by estrogen and is positively associated with estrogen receptor expression, although its molecular role remains unclear. Proteomics was used to identify SGK3's downstream targets. Tissue microarray immunofluorescence evaluated SGK3 and ZMIZ2 expression in ER+ breast cancer. Lentiviral-mediated knockdown and overexpression of SGK3 and/or ZMIZ2 assessed their effects on cell proliferation in vitro and in vivo. Chromatin immunoprecipitation (ChIP) analyzed p-STAT3 binding to the ZMIZ2 promoter, and Co-immunoprecipitation (Co-IP) examined ZMIZ2-β-catenin interaction. SGK3 expression was elevated in breast tumour tissues correlating with reduced patient survival. Proteomic analysis identified ZMIZ2 as a downstream target of SGK3. Overexpression of SGK3 promoted the proliferation of estrogen receptor-positive breast cancer in MCF-7 and T47D cells. Inhibition had the opposite effects. ZMIZ2 overexpression rescued the proliferation deficit in SGK3 knockdown cells. ZMIZ2 was found to bind and stabilises β-catenin. Knockdown of SGK3 led to β-catenin degradation via polyubiquitination, a process reversed by ZMIZ2 overexpression. STAT3 was identified as a downstream effector of SGK3 and its knockdown reduced cytoplasmic and nuclear p-STAT3 and STAT3, and inhibited ZMIZ2 and β-catenin expression. Celastrol suppressed estrogen receptor-positive breast cancer cell proliferation by inhibiting the SGK3/STAT3/ZMIZ2/β-catenin pathway. SGK3 expression is associated with poorer survival rates, thus SGK3 is a potential therapeutic target. As celastrol can inhibit SGK3 expression it could be an effective therapeutic agent.

New Oral Selective Estrogen Receptor Degraders Redefine Management of Estrogen Receptor-Positive Breast Cancer.

Oral selective estrogen receptor degraders (SERDs) are pure estrogen receptor antagonists that have the potential to overcome common resistance mechanisms to endocrine therapy in estrogen receptor-positive breast cancer. There are currently five oral SERDs in published and ongoing clinical trials-elacestrant, camizestrant, giredestrant, imlunestrant, and amcenestrant-with more in development. They offer a reasonably well-tolerated oral therapy option with low discontinuation rates in studies. This review summarizes the currently available literature on this new class of drugs.

RET inhibition overcomes resistance to combined CDK4/6 inhibitor and endocrine therapy in ER+ breast cancer

BackgroundCombined CDK4/6 inhibitor (CDK4/6i) and endocrine therapy significantly improve the outcome of patients with advanced estrogen receptor-positive (ER+) breast cancer. However, resistance to this treatment and disease progression remains a major clinical challenge. High expression of the receptor tyrosine kinase REarranged during Transfection (RET) has been associated with resistance to endocrine therapy in breast cancer, but the role of RET in CDK4/6i treatment response/resistance remains unexplored.MethodsTo identify gene expression alterations associated with resistance to combined endocrine therapy and CDK4/6i, we performed RNA sequencing of two ER+ breast cancer cell models resistant to this combined therapy. The functional role of RET was assessed by siRNA-mediated RET silencing and targeted inhibition with the FDA/EMA-approved RET-selective inhibitor selpercatinib in resistant breast cancer cells and patient-derived organoids (PDOs). RET silencing was evaluated mechanistically using global gene expression and pathway analysis. The clinical relevance of RET expression in ER+ breast cancer was investigated by gene array analysis of primary tumors treated with endocrine therapy and by immunohistochemical scoring of metastatic lesions from patients who received combined CDK4/6i and endocrine therapy.ResultsWe show that RET is upregulated in ER+ breast cancer cell lines resistant to combined CDK4/6i and fulvestrant compared to isogenic cells resistant to fulvestrant alone. siRNA-mediated silence of RET in high RET-expressing, combined CDK4/6i- and fulvestrant-resistant cells reduced their growth partially by affecting cell cycle regulators of the G2-M phase and E2F targets. Notably, targeting RET with selpercatinib in combination with CDK4/6i inhibited the growth of CDK4/6i-resistant cell lines and resensitized ER+ breast cancer patient-derived organoids resistant to CDK4/6i. Finally, analysis of RET expression in ER+ breast cancer patients treated with endocrine therapy showed that high RET expression correlated with poor clinical outcomes. We further observed a shorter median survival to combined CDK4/6i and endocrine therapy in patients with RET-positive compared to RET-negative tumors, but this difference did not reach statistical significance.ConclusionsOur findings show that RET is overexpressed in ER+ metastatic breast cancer resistant to combined CDK4/6i and endocrine therapy, rendering RET inhibition a promising therapeutic approach for patients who experience disease progression on combined CDK4/6i and endocrine therapy.

Long-Term Outcomes of Radiation Monotherapy Versus Combined Radiation Monotherapy + Hormone Therapy in Low-Risk Early-Stage Breast Cancer Patients 70 Years or Older After Breast-Conserving Surgery.

Standard therapy for breast cancer after breast-conserving surgery is radiation therapy (RT) plus hormone therapy (HT). For patients with a low-risk of recurrence, there is an interest in deescalating therapy. A retrospective study was carried out for patients treated at the Swedish Cancer Institute from 2000 to 2015, aged 70 years or older, with pT1N0 or pT1NX estrogen receptor-positive and ERBB2-negative unifocal breast cancer without positive surgical margins, high nuclear grade, or lymphovascular invasion. Patient numbers were sufficient to carry out analyses for RT + HT (n = 307) and RT alone (n = 148). The median follow-up was 9.6 years. There were no statistically significant differences in adjusted overall survival (OS), disease-specific death, progression-free survival (PFS), distant recurrence, and second primary cancers with RT monotherapy compared with RT + HT. Cumulative rates of all of these outcomes were <5%, even at 15 years of follow-up, regardless of treatment, greatly outweighed by the incidence of death from other causes in this elderly population. In matched analysis, we calculated a hazard ratio of 1.12 (95% CI, 0.82-1.53) for RT versus RT + HT for OS and a hazard ratio of 1.12 (95% CI, 0.82-1.53) for RT versus RT + HT for PFS. Our data suggest that elderly, low-risk breast cancer patients have similarly high OS and PFS with low rates of local recurrence, distant recurrence, and death from breast cancer with much higher rates of death from competing causes, whether treated with RT or HT + RT. These patients are likely to die of other causes without disease recurrence, regardless of which of these treatments is used. Thus, they may benefit from the administration of more modern forms of breast irradiation without the need for adjuvant systemic hormone therapy. A detailed analysis of which clinical, pathologic, genomic, and comorbidity variables are needed to select these patients.

HGF/c-Met Promotes Breast Cancer Tamoxifen Resistance Through the EZH2/HOTAIR-miR-141/200a Feedback Signaling Pathway.

Tamoxifen is one of the most frequently used endocrine medications for the treatment of estrogen receptor-positive (ER + ) breast cancer (BC). Unfortunately, tamoxifen resistance (TR) brings more challenges to the clinical treatment, and the mechanisms of TR have not yet been fully clarified. HGF/c-Met is closely associated with cancer metastasis, but whether it is involved in TR remains unclear. In our study, we found that the activation of HGF/c-Met was crucial for TR maintenance. Synergistic interaction with HOTAIR and EZH2 accelerated HGF expression by repressing miR-141/200a. Additionally, HGF/c-Met activated NF-κB, forming a positive feedback loop of EZH2/HOTAIR-miR-141/200a-HGF/c-Met-NF-κB. Our findings indicated that HGF/c-Met functioned as an important biomarker for TR, and HGF/c-Met inhibition provided a novel approach to TR treatment.

PARP12-mediated ADP-ribosylation contributes to breast cancer cell fate by regulating AKT activation and DNA-damage response

Breast cancer represents the primary cause of death of women under 65 in developed countries, due to the acquisition of multiple drug resistance mechanisms. The PI3K/AKT pathway is one of the major regulating mechanisms altered during the development of endocrine resistance and inhibition of steps in this signalling pathway are adopted as a key strategy to overcome this issue. ADP-ribosylation is a post-translational modification catalysed by PARP enzymes that regulates essential cellular processes, often altered in diseases. PARP12, a member of this family, has been associated with the onset of drug resistance in oestrogen receptor-positive breast cancers, making this enzyme a promising drug target. The molecular basis underlying its involvement in the acquisition of resistance are unknown to date. Here, we demonstrate that PARP12-mediated mono-ADP-ribosylation of AKT is required for AKT activation whilst the absence of PARP12 leads to apoptosis induction in a subset of oestrogen receptor-positive breast cancer cells. Our data show that transcriptional inhibition of PARP12 correlates with an increased DNA-damage induction, mirrored by augmented p53 nuclear localisation and enhanced p53-AKT interaction. Under these conditions, AKT is functionally incompetent towards its downstream targets FOXO, hence favouring cell death. This is achieved by increasing protein levels of the FOXO1 transcription factor, that in turn activates the apoptotic cascade. Overall, we show a novel regulation step of AKT activation and apoptosis relying on PARP12-mediated mono-ADP-ribosylation and propose PARP12 as a potential pharmacological target to be exploited as an innovative therapeutical strategy to overcome endocrine resistance.

Diagnostic Value of Gastrin-Releasing Peptide Receptor-Targeted PET Imaging in Oncology: A Systematic Review.

Gastrin-releasing peptide receptor (GRPR), overexpressed in various cancers, is a promising target for positron emission tomography (PET). This systematic review investigated the diagnostic value of GRPR-targeted PET imaging in oncology. A systematic search was conducted on major medical databases until May 23, 2024. Keywords were modified to include clinical original studies on GRPR-targeted PET in cancer patients. Out of 1624 searched studies initially, 107 were eligible for the full-text review. Overall, data from 38 studies met inclusion criteria, investigating GRPR-targeting radiotracers in breast cancer, prostate cancer, gastrointestinal stromal tumours (GIST) and gliomas (including optic pathway glioma and glioblastoma multiforme). In breast cancer, GRPR-targeted PET effectively detected primary tumours and metastases, particularly in estrogen receptor (ER)-positive patients, and predicted treatment response. In prostate cancer, high sensitivity (up to 88%) and specificity (up to 90%) for detecting primary tumours were observed, providing added value when combined with magnetic resonance imaging (MRI). In biochemical recurrence, sites of prostate cancer were identified even at PSA levels below 0.5ng/dL. Compared with PSMA PET, GRPR-targeted PET showed comparable or superior detection rates. Considering GIST, GRPR-targeted PET imaging proved to be a valuable diagnostic tool, particularly when [18F] FDG PET results were inconclusive. Regarding gliomas, GRPR-targeted PET achieved a 100% detection rate (MRI reference), aiding localization, preoperative planning, and differentiation between recurrence and malignant transformation. GRPR-targeted PET shows promise in improving cancer diagnostics, particularly in ER-positive breast cancer, prostate cancer, and gliomas, and may enhance clinical decision-making.

Intrapatient 16α-[18F]Fluoro-17β-Estradiol PET Heterogeneity as a Prognostic Factor for Endocrine Therapy Response and Survival in Patients with Estrogen Receptor-Positive Metastatic Breast Cancer.

Intrapatient heterogeneity of estrogen receptor (ER) expression on 16α-[18F]fluoro-17β-estradiol ([18F]FES) PET is related to outcome in patients with ER-positive metastatic breast cancer (MBC), but a validated and practical method to support clinical decision-making is lacking. Therefore, the [18F]FES PET heterogeneity score (i.e., percentage of [18F]FES-positive metastases) was validated as a prognostic factor for endocrine therapy response and survival in a large cohort of patients with newly diagnosed MBC. Furthermore, we explored 2 less laborious methods to predict the [18F]FES PET heterogeneity score. Methods: Patients with ER-positive MBC included in the IMPACT-MBC study, who received baseline [18F]FES and [18F]FDG PET and first-line endocrine therapy, were included in this subanalysis. ER homogeneous (100% [18F]FES-positive lesions) and ER heterogeneous (both [18F]FES-positive and [18F]FES-negative lesions) MBC was distinguished by manual segmentation of all lesions on [18F]FES PET and related to progression-free survival (PFS) and overall survival (OS). In addition, the positive predictive value of the visual assessment and the 5-largest-lesions assessment to predict homogeneous MBC in all lesions on [18F]FES PET was determined. Results: From the 102 MBC patients eligible for the present retrospective subanalysis, 46 had ER homogeneous MBC and 56 had ER heterogeneous MBC. Differences were found between ER homogeneous and ER heterogeneous MBC for median PFS (19.8 vs. 15.0 mo; hazard ratio, 0.63; 95% CI, 0.41-0.96; P = 0.03) and median OS (62.5 vs. 34.7 mo; hazard ratio, 0.65; 95% CI, 0.38-1.08; P = 0.09). Twenty-one (38%) of 61 patients with ER homogeneous MBC by visual analysis and 37 (45%) of 83 patients with ER homogeneous MBC by the 5-largest-lesions method had ER heterogeneous MBC by manual segmentation of all lesions on [18F]FES PET (positive predictive value, 0.66 and 0.55, respectively). Conclusion: Patients with ER-positive homogeneous MBC showed a trend toward superior PFS and OS compared with patients with ER heterogeneous MBC. This analysis confirmed and validated the prognostic value of the [18F]FES PET heterogeneity score for endocrine therapy response and survival in a large cohort of MBC patients. The less laborious visual and 5-largest-lesions methods were inferior compared with assessment based on the [18F]FES PET heterogeneity score in all lesions.