Hormone-sensitive Breast Cancer Research Articles

Neurotensin and Its Involvement in Female Hormone-Sensitive Cancers

Neurotensin (NT) is a peptide involved in digestion, neuromodulation, and cancer progression. NT and its receptors (NTR1 and SORT1 mainly) have been widely studied in oncology. Data show that NT expression is under the control of sex steroid hormones, in particular estradiol. We focused on its involvement in three main female hormone-sensitive cancers, breast, ovarian, and endometrial cancer, in a narrative review. NT, NTR1, and SORT1 are mostly expressed in these three cancers, and their involvement in oncologic processes such as proliferation and invasion seems to match, as does their impact on prognosis for most. The development of NT receptor-targeted therapies, including theranostics and radioligand treatments, presents a promising avenue for personalized cancer treatment.

Further Optimizing Care of Patients With Operable Hormone Receptor-Sensitive Breast Cancer.

Harmonized global collaborations are crucial to improving outcomes in hormone sensitive operable breast cancer.

Assessing outcomes for patients receiving chemotherapy in the intensive care unit.

190 Background: Despite the low in-hospital mortality rate (9%) for Intensive Care Unit (ICU) stays in the US, outcomes for patients with cancer undergoing chemotherapy in the ICU remains unclear. We aimed to assess survival in patients with cancer (liquid, solid tumor and allogeneic stem cell transplant (alloSCT) receiving chemotherapy at our institution and identify patient characteristics for enhanced chemotherapy stewardship. Methods: We analyzed pharmacy data for patients with confirmed malignancies who received chemotherapy while admitted to the ICU at our institution from 1/1/21 to 12/31/23, excluding non-cancer patients and those on home oral regimens. Primary endpoints included 14-day, 30-day, and 90-day survival. Secondary analyses examined survival differences by age, ECOG performance status, and treatment history. Survival differences among patient subtypes were evaluated using Z-tests. Results: We identified 74 unique patients who received chemotherapy for cancer. 54 had liquid tumors, 5 were post-alloSCT, and 15 had solid tumors. The 90-day survival rate was 47% overall: 46% for the liquid tumor group, 80% for the alloSCT group, and 40% for the solid tumor group. When further stratified by tumor type, higher 90-day survival was variable; see Table 1 for details). In patients with lung cancer, 90-day survival was worse for non-small cell lung cancer without tumor mutations (0%, n=2) than those with targetable mutations (50%, n=4) or small cell lung cancer (33%, n=3). An ECOG performance status of 3-4 showed poorer 90-day survival in liquid tumors (23%) compared to ECOG 1-2 (74%; 95% CI 0.26 , 0.76). Solid tumors showed no significant ECOG differences (50%, 40%). Treatment-naive status showed higher 90-day survival in liquid tumors (59%) compared to treatment-resistant tumors (18%; 95% CI 0.17, 0.65), but not in solid tumors (50%, 20%). Conclusions: Our findings suggest generally unfavorable 90-day outcomes for ICU chemotherapy patients, especially those aged over 75, with multiple therapy lines, or ECOG status 3-4. Survival rates varied significantly across tumor types. We are currently broadening our study to include all solid tumor cancer patients. While this is a limited sample, this underscores the need for careful chemotherapy stewardship and advanced care planning in ICU settings. 90-day survival of solid and liquid tumor patients receiving chemotherapy in the ICU by select cancer diagnoses. Cancer Diagnosis n 90-Day Survival (%) AML 20 45 DLBCL 16 33 APML 6 83 Multiple myeloma 5 60 Other liquid tumors 1 11 45 Lung cancer 9 44 Germ cell tumor 2 100 Hormone-sensitive breast cancer 1 100 Other solid tumors 2 3 0 1 T-cell lymphoma, ALL, CNS lymphoma, Castleman, MPN, and plasmablastic lymphoma. Note, patients with allogenic stem cell transplants not included. 2 Carcinoma of unknown primary, colon adenocarcinoma, multiple solid tumors.

Effects of Adjuvant Endocrine Therapy-Specific Perceptions on Response to a Behavioral Intervention for Adjuvant Endocrine Therapy Adherence in Patients With Breast Cancer.

Adjuvant endocrine therapy (AET) is a life-saving medication for patients with hormone-sensitive breast cancer, yet many struggle with adherence, warranting behavioral intervention. In our recent trial, participation in a group cognitive behavioral intervention (STRIDE) for symptom management and adherence was associated with improvements in symptom distress, coping, quality of life, and mood. We now explore whether baseline patient- and medication-specific factors-which may be modifiable by clinician-led discussions-moderated the effect of STRIDE on adherence rates. From October 2019 to June 2021, 100 patients with early-stage breast cancer reporting AET-related distress were enrolled and randomly assigned to STRIDE or a medication monitoring (MM) control group. All patients stored their AET in electronic pill bottles to track objective adherence. Patients also self-reported their adherence on the Medication Adherence Report Scale-5 and their perceptions of AET on the Cancer Therapy Satisfaction Questionnaire at baseline. We conducted hierarchical linear modeling to test moderators of intervention effects on objective adherence rates. We report the time × group × moderator effects. Among patients reporting greater perceived difficulties with AET adherence at baseline, STRIDE participants had higher adherence rates over time compared with MM (b = -13.80; SE = 4.56; P < .01). Patients with greater expectations of therapeutic benefit from AET also had improved adherence rates if they were assigned to STRIDE, versus MM (b = 0.25; SE = 0.10; P = .01). Patients who perceived taking AET as convenient and had been taking their AET for less time had higher adherence rates in STRIDE, versus MM. The current study identified patient- and medication-specific factors that may augment AET adherence interventions and may be modifiable through clinician-led discussions, such as perceptions of adherence problems, therapeutic efficacy, and convenience of AET.

Acetylation of Steroidogenic Acute Regulatory Protein Sensitizes 17β-Estradiol Regulation in Hormone-Sensitive Breast Cancer Cells.

An imbalance in estrogen signaling is a critical event in breast tumorigenesis. The majority of breast cancers (BCs) are hormone-sensitive; they majorly express the estrogen receptor (ER+) and are activated by 17β-estradiol (E2). The steroidogenic acute regulatory protein (StAR) mediates the rate-limiting step in steroid biosynthesis. The dysregulation of the epigenetic machinery, modulating E2 levels, is a primary occurrence for promoting breast tumorigenesis. StAR expression, concomitant with E2 synthesis, was reported to be aberrantly high in human and mouse hormone-dependent BC cells compared with their non-cancerous counterparts. However, the mechanism of action of StAR remains poorly understood. We discovered StAR as an acetylated protein and have identified a number of lysine (K) residues that are putatively acetylated in malignant and non-malignant breast cells, using LC-MS/MS (liquid chromatography-tandem mass spectrometry), suggesting they differently influence E2 synthesis in mammary tissue. The treatment of hormone-sensitive MCF7 cells with a variety of histone deacetylase inhibitors (HDACIs), at therapeutically and clinically relevant doses, identified a few additional StAR acetylated lysine residues. Among a total of fourteen StAR acetylomes undergoing acetylation and deacetylation, K111 and K253 were frequently recognized either endogenously or in response to HDACIs. Site-directed mutagenesis studies of these two StAR acetylomes, pertaining to K111Q and K253Q acetylation mimetic states, resulted in increases in E2 levels in ER+ MCF7 and triple negative MB-231 BC cells, compared with their values seen with human StAR. Conversely, these cells carrying K111R and K253R deacetylation mutants diminished E2 biosynthesis. These findings provide novel and mechanistic insights into intra-tumoral E2 regulation by elucidating the functional importance of this uncovered StAR post-translational modification (PTM), involving acetylation and deacetylation events, underscoring the potential of StAR as a therapeutic target for hormone-sensitive BC.

The Glucose-Glutamine Metabolic Interplay in MCF-7 Cells, a Hormone-Sensitive Breast Cancer Model.

Selective deprivation of glutamine has been shown to accelerate the generation of reactive oxygen species (ROS) and to impair the activity of a specific pentose phosphate pathway (PPP) located within the endoplasmic reticulum (ER). The consequent oxidative damage suggests that glucose flux through this reticular pathway might contribute to the redox stress of breast cancer cells. We thus evaluated whether this response is reproduced when the glutamine shortage is coupled with the glucose deprivation. Cancer growth, metabolic plasticity and redox status were evaluated under saturating conditions and after 48 h starvation (glucose 2.5 mM, glutamine 0.5 mM). The Seahorse technology was used to estimate adenosine triphosphate (ATP)-linked and ATP-independent oxygen consumption rate (OCR) as well as proton efflux rate (PER). 18F-fluoro-deoxy-glucose (FDG) uptake was evaluated through the LigandTracer device. Proliferation rate was estimated by the carboxyfluorescein-diacetate-succinimidyl ester (CFSE) staining, while cell viability by the propidium iodide exclusion assay. Starvation reduced the proliferation rate of MCF-7 cells without affecting their viability. It also decreased lactate release and PER. Overall OCR was left unchanged although ATP-synthase dependent fraction was increased under nutrient shortage. Glutaminolysis inhibition selectively impaired the ATP-independent and the oligomycin-sensitive OCR in control and starved cultures, respectively. The combined nutrient shortage decreased the cytosolic and mitochondrial markers of redox stress. It also left unchanged the expression of the reticular unfolded protein marker GRP78. By contrast, starvation decreased the expression of hexose-6P-dehydrogenase (H6PD) thus decreasing the glucose flux through the ER-PPP as documented by the profound impairment in the uptake rate of FDG. When combined with glucose deprivation, glutamine shortage does not elicit the expected enhancement of ROS generation in the studied breast cancer cell line. Combined with the decreased activity of ER-PPP, this observation suggests that glutamine interferes with the reticular glucose metabolism to regulate the cell redox balance.

Endoxifen Concentration is Associated with Recurrence-Free Survival in Hormone-Sensitive Breast Cancer Patients.

The metabolism of tamoxifen is influenced by various cytochrome p450 enzymes, including CYP2D6 and CYP2C19, leading to variations in the levels of endoxifen, even with the same tamoxifen dosage. However, the clinical significance of endoxifen on the prognosis of breast cancer patients remains controversial. This study aimed to elucidate the relevance of endoxifen level to recurrence-free survival censored with tamoxifen discontinuation (RFSt), representing the RFS for tamoxifen itself, of breast cancer patients and determine a suitable cutoff for prognostication. The study included 478 breast cancer patients, and tamoxifen and its metabolites, including endoxifen, were measured using liquid chromatography-tandem mass spectrometry (LC-MS/MS). An optimal cutoff was determined with maximally selected rank statistics. Survival analysis and Cox regression were conducted based on this cutoff. An endoxifen level of 21.00 ng/mL was the optimal cutoff for prognostication. Survival analysis revealed a statistically significant difference in RFSt between the low endoxifen group (≤ 21.00 ng/mL) and high endoxifen group (> 21.00 ng/mL) (log-rank test, p=0.032). The 10-year probability of RFSt was 83.2% (95% CI, 77.0-89.9%) and 88.3% (95% CI, 83.3-93.5%) in the low and high endoxifen groups, respectively. Multivariable Cox proportional hazards regression indicated endoxifen concentration as a significant factor affecting prognosis, which was adjusted with other clinical characteristics. Endoxifen could serve as a marker for appropriate tamoxifen treatment, and an endoxifen cutoff of 21.00 ng/mL could be advantageous in prognostication. Based on this cutoff, therapeutic drug monitoring would benefit patients displaying a suboptimal concentration.

Adherence to adjuvant hormone therapy in hormone-sensitive breast cancer: Insights from the Medical Oncology Department at Hassan II University Hospital, Morocco.

e12505 Background: Adjuvant endocrine therapy (AET) improves long-term survival for hormone-sensitive breast cancer; However, suboptimal adherence is prevalent, with many women failing to follow prescribed dosage and frequency. Long-term adherence patterns to AET are poorly understood. Additionally, there is a lack of data regarding the adherence to AET among Moroccan women and the factors that may influence it. Objectives: The primary objective of the study was to assess the adherence rate to AET in patients with HR-positive early breast cancer being treated at Hassan II University Hospital of Fez, Morocco. Secondary objectives included determining factors associated with poor adherence and assessing the adverse events associated with AET and their prevalence. Methods: We conducted a cross-sectional study involving 335 breast cancer patients undergoing AET. Eligible patients, who had received at least one dispensing of AET, participated in the study through a direct questionnaire survey after providing signed consent. The questionnaire comprised sections covering patient demographics, clinical data (stage, type of AET, duration of therapy), side effects or symptoms related to AET, other factors that may impact adherence. Adherence to AET was assessed at three points of measurement: 1 year, 3 years, and ≥ 5 years after the initiation of therapy. The study was carried out with respect to the Moroccan regulation in effect. Results: The study included 335 cases with an average age of 54 years. Participants were predominantly illiterate (62%) and post-menopausal (50.7%). Most were classified as stage II UICC (53.5%). Mastectomy was performed in the majority (74%). Neo(adjuvant) CMT was given to 79.4%, and adjuvant radiotherapy to 86.9%. Tamoxifen was administered to 55.4%, and aromatase inhibitors to 44.6%. Medical castration was associated with 12.5%, and 35 patients switched AET over time. Only 12.8% exceeded 5 years of AET during recruitment. Adherence assessment revealed an overall adherence rate of 53.4%. Notably, 67.2% claimed never to forget their medication, and about 20% temporarily stopped it, primarily due to lack of information. Most participants used a reminder strategy, notably alarms (43.3%). Treatment tolerance varied, with hot flushes and arthralgia being predominant side effects. Statistical analyses found a significant link between treatment lasting over 5 years and non-adherence (p = 0.003). However, the use of an alarm as a reminder strategy strengthened adherence (p = 0.021). No statistically significant differences were noted in other variables. Conclusions: Despite the benefits, ensuring adjuvant hormone therapy adherence is challenging. Our analysis, estimating a 53.4% global adherence, found that only treatment duration and recall strategy significantly correlated with adherence.

Sexual health and therapy adherence of hormone-sensitive breast cancer survivors on maintenance endocrine therapy: The SHE-CAN project in Toronto, Canada.

536 Background: Endocrine therapy (ET) is the standard of care for hormone sensitive (HR) breast cancer. While these drugs are highly efficacious and patients remain on them for extended periods of time, there are many side effects. It is estimated that 20-30% of women on ET stop early due to these side effects, most commonly due to gynecological symptoms of menopause (GSM). The purpose of this study is to better understand the vaginal health, sexual health, quality of life, sexual dysfunction, and adherence to therapy for HR breast cancer patients treated with anti-estrogen therapy. Methods: From August 2021 to January 2024, women from Mount Sinai Hospital’s outpatient oncology clinic and Women’s College Hospital After Cancer Treatment Transition (ACTT) clinic, who presented with HR breast cancer and who were being treated with anti-estrogen agents for a minimum of three months, were invited to participate in the study. Participants were asked to complete a survey examining their treatment experience and adherence, occurrence and frequency of GSM, patient-provider communication, along with two validated measurement tools (Female Sexual Function Index [FSFI} and Menopause-Specific Quality of Life questionnaire [MENQOL]). Medical history was also reviewed from the participant’s medical chart. Analysis was conducted using Excel. Results: A total of 417 participants completed the questionnaire. The median age was 60 years [IQR:52-69] with 401 participants (96.2%) being treated in the adjuvant setting versus 16 patients (3.8%) in the metastatic setting. At the time of diagnosis, 156 participants (37.4%) were pre-menopausal, 52 participants (12.5%) were peri-menopausal, and 185 participants (44.4%) were post-menopausal. When surveyed, 134 participants (32.1%) were on tamoxifen and 272 participants (65.2%) were on an aromatase inhibitor. Within six months prior to survey completion, 214 participants (51.3%) stopped taking their medication for a period of time. Within the past year, participants reported experiencing the following symptoms “all of the time”: vaginal dryness (24.9%), hot flashes (24.7%), and decreased sex drive (34.5%). Only 144 participants (34.5%) reported that a healthcare provider had asked them about experiencing GSM. The mean FSFI score was 21.9 ± 7.7 among 168 sexually active participants. Of these 168 participants, 116 (69.0%) had a final score of 26.5 or less, the cut-point used to demonstrate female sexual dysfunction. Symptoms captured in the MENQOL’s sexual domain (3.7 ± 2.3) and physical domain (3.7 ± 1.4) were found to be most bothersome. Conclusions: In our study, patients with breast cancer on ET report significant sexual dysfunction. Management of GSM and improved communication between patients and healthcare providers is required and should be prioritized to improve sexual dysfunction and treatment adherence.

Exploring factors impacting quality of life in patients with breast cancer undergoing adjuvant hormone therapy: Experience of the Medical Oncology Department-CHU Hassan II-FEZ University Hospital.

e12507 Background: Considering that the recommended duration of adjuvant hormone therapy in localized breast cancer is at least 5 years, it becomes crucial to investigate the quality of life (QOL) of these patients and the factors influencing it. Objectives: To assess the quality of life (QOL) and identify factors impacting it in patients with localized hormone-sensitive breast cancer receiving adjuvant hormone therapy. Methods: We surveyed 335 patients with localized hormone-sensitive breast cancer undergoing adjuvant hormone therapy using the Moroccan Arabic dialect version of the EORTC QLQ-C30 questionnaire. Written informed consent was obtained from all participants. Confidentiality of participant data was maintained. The study was carried-out with respect to the Moroccan regulation in effect. Results: The overall quality of life (QOL) in our patient population was moderate, with positive scores for social functioning, followed by physical, cognitive, and emotional functioning. Financial difficulties emerged as the most influential factor affecting patients' QOL, followed by fatigue, pain, and other symptoms. Age-related declines in physical functioning were observed, with symptoms more prevalent, especially diarrhea, in patients aged 70 and above (p = 0.009). Urban patients faced a greater financial impact on QOL than rural patients (p = 0.025). Higher education correlated with improved QOL, particularly in physical functioning (p = 0.025). Married individuals demonstrated better overall QOL and fewer symptoms (p = 0.027). Menopausal patients exhibited lower ability and a higher loss of appetite (p = 0.027). No significant correlation was found between UICC stage and QOL. Patey-mastectomy was associated with more pain than tumorectomy (p = 0.024). Previous chemotherapy had no overall QOL impact, but users reported less diarrhea (p = 0.016). Hormone therapy type did not significantly affect overall health status, except for tamoxifen users who demonstrated improved functional roles (p = 0.008). The duration of adjuvant hormone therapy (&lt;5 years or &gt;5 years) showed no significant difference in patient QOL. Associated castration had a significant impact on overall health and role functioning, favoring non-castration (p = 0.034 and p = 0.011). Effective treatment tolerance positively influenced overall QOL, leading to better physical, emotional, and cognitive functioning (p &lt; 0.0001), with fewer pronounced symptoms. Conclusions: Our study indicate that the overall QOL of patients with localized breast cancer under AET was moderate, and several factors were identified as major influences, each affecting the QOL in distinct ways.

Effectiveness of cyclin-dependent kinase 4 and 6 inhibitors for the treatment of hormonesensitive HER2-negative metastatic breast cancer in first-line therapy: A systematic literature review

At present, cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors such as palbociclib, ribociclib, and abemaciclib are widely used for the first-line treatment of locally advanced or metastatic breast cancer. However, direct comparisons of these treatment options in randomized studies have not been conducted.Aim of the work is to gather and analyze published data on the comparative effectiveness of CDK4/6 inhibitors in combination with aromatase inhibitors in postmenopausal patients with HR+/HER2– locally advanced or metastatic breast cancer. A systematic review of publications presenting results from original studies on the impact of CDK4/6 inhibitor therapy in combination with aromatase inhibitors on the survival of patients was performed. Nineteen studies with original data on progression-free survival and overall survival were identified. None of the studies found significant differences between different CDK4/6 inhibitors and aromatase inhibitors in terms of progression-free survival. A statistically significant superiority of ribociclib over palbociclib in terms of overall survival was observed in a single matching-adjusted indirect comparison, while seven other studies of various types (real-world data studies, matching-adjusted indirect comparisons, and meta-analyses) did not find significant differences between the investigated drugs in terms of overall survival.Currently, there is no compelling evidence of the superiority of one CDK4/6 inhibitor over others. The decision on the preference for a specific drug within the class can only be made after conducting direct randomized comparison trials, or accumulating sufficient real-world data on the use of palbociclib, ribociclib, and abemaciclib.

Abstract PO3-20-02: Olaparib front line therapy with endocrine therapy in locally advanced unresectable or in metastatic breast cancer: OFELIA TRIAL

Abstract INTRODUCTION: Currently, patients with recurrent or metastatic hormone-sensitive breast cancer are treated with endocrine therapy (ET) in combination with cyclin inhibitors, as it has been shown to improve both overall survival and progression-free survival. However, it has been observed that patients with gBRCA1 or gBRCA2 mutations, who receive treatment with endocrine therapy and CDK4/6 inhibitors, have lower OS and lower PFS compared to those without mutations. These findings could be due to the presence of higher cyclin E mRNA levels, which encode the protein that stimulates CDK2 activity provoking a resistance to CDK4/6 inhibitors. Having this said, the use of PARP inhibitors a potential first-line therapeutic option in combination with endocrine therapy could be an option to be re evaluated. JUSTIFICATION: PARP inhibitors (iPARP) are recommended in international guidelines as second-line palliative treatment and also as adjuvant management in the case of Olaparib. The use of iPARP is approved only as a second-line treatment in HER2 hormone-sensitive breast cancer, according to the results of the EMBRACA and OlympiAD clinical trials. However, these two clinical trials were not designed to evaluate its effectiveness as first-line palliative treatment. Given that patients with gBRCA mutations have lower overall survival when administered cyclin inhibitors (iCDK 4/6) + Endocrine therapy (ET) compared to those without mutations, it is necessary to reevaluate the use of iPARP as first-line palliative treatment in conjunction with ET, with the expectation of achieving a similar objective response rate and progression-free survival. OBJECTIVE: To Determine the ORR in patients with recurrent or metastatic hormone-sensitive HER2-negative breast cancer managed with PARP inhibitors + Endocrine therapy. HYPOTHESIS: The use of PARP inhibitors in combination with endocrine therapy will have an objective response rate of 60% or higher in both early stages and advanced disease. METHODOLOGY: Phase 2 open-label, multicenter clinical trial. Study Population: Cohort : All pre- or postmenopausal patients with a diagnosis of recurrent or metastatic hormone-sensitive HER2-negative breast cancer with gBRCA1 and/or gBRCA2 mutation. Sample: The inclusion of patients will be based on meeting the inclusion criteria. We plan to achieve an ORR of at least 60% with an acceptable minimum of 40%. Assuming a one-sided alpha level of 0.05 and statistical power of 80%, a two-stage Simon design was used to calculate the required sample size. In the first stage, a minimum of 23 patients is assumed, of which 14 patients need to achieve the desired response rate to proceed to the second stage. In the second stage, an additional 28 patients will be added to obtain a total sample size of 51 patients. The objective response rate will be evaluated using RECIST v1.1 criteria at 8 weeks after initiating treatment, with continued assessment during the first year, followed by assessments every 12 weeks during the second and third year, and then every 24 weeks until progression or toxicity. EXPECTED RESULTS: PARP inhibitors + Endocrine therapy will have a similar ORR as reported with cyclin inhibitors + Endocrine therapy, as well as a benefit in progression-free survival. Citation Format: Carlos Arturo González Núñez, Paula Cabrera-Galeana, Juan Enrique Bargalló Rocha, Rafael Vazquez-Romo, Sergio Aguilar-Villanueva, Alexandra Garcilazo, Areli Velazquez-Martinez, Andrea Maliachi, Ruben Rodriguez. Olaparib front line therapy with endocrine therapy in locally advanced unresectable or in metastatic breast cancer: OFELIA 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 PO3-20-02.

Abstract PO3-16-04: Distribution of intrinsic subtypes in endocrine-resistant and endocrine-sensitive breast cancer

Abstract Background Breast cancer (BC) is a heterogeneous disease that can be divided into intrinsic molecular subtypes. Among the four intrinsic subtypes, Luminal A and Luminal B are the most common and associated with the best outcome, whereas HER2-enriched and basal-like are less frequent. Tumors that are estrogen receptor α (ER)-positive and human epidermal growth factor receptor 2 (HER2)-negative (ER+/HER2-) are mostly found among the luminal subtypes. Despite that patients with ER+/HER2- tumors are offered adjuvant endocrine therapy, around one-third eventually develop endocrine resistance. The aim of this study was to explore the distribution of intrinsic subtypes in endocrine-resistant primary and relapse tumors, comparing these to endocrine-sensitive controls. Materials and methods Verified endocrine-resistant BC patients diagnosed in 2008-2012 were retrospectively collected at the Karolinska University Hospital, Stockholm, Sweden. Cases (N=70) were identified as patients with ER+/HER2- primary tumors and subsequent ER+/HER2- relapse tumors within 5 years and during endocrine therapy. Patients with primary ER+/HER2- tumors without progression or relapse at 10 years of follow-up were defined as controls (N=78), diagnosed in 2005-2006. Extracted RNA from formalin-fixed paraffin-embedded tumor tissue was analyzed by Affymetrix Clariom D Microarray and assessed by Transcriptome Analysis Console and R software. Results Among the controls, the distribution of Luminal A, Luminal B, and HER2-enriched subtypes was 65.4%, 34.6%, and 0%, respectively. In primary tumors, the distribution was in turn 55.4%, 43.1%, and 1.5%, and among relapse tumors 57.6%, 37.9%, and 4.5%, respectively. A total of 19 cases, accounting for 27.1%, switched intrinsic subtypes between the paired primary and relapse tumors. No tumors exhibited the basal-like subtype. Conclusion In this unique cohort, Luminal B and HER2-enriched subtypes were more common in primary and relapse tumors of verified endocrine-resistant patients than in primary tumors of endocrine-sensitive controls. Further, the HER2-enriched subtype, although sparse, was more frequently found in patients’ relapse tumors than in their corresponding primary tumors, and over one-fourth of cases switched subtypes during progression. These findings support the presence of subtype shifting in endocrine-resistant relapses and that endocrine-resistant tumors are more prone to be of Luminal B or HER2-enriched subtypes than endocrine-sensitive tumors. Citation Format: Caroline Schagerholm, Stephanie Robertson, Emelie Karlsson, Emmanouil Sifakis, Johan Hartman. Distribution of intrinsic subtypes in endocrine-resistant and endocrine-sensitive 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 PO3-16-04.

Abstract PO1-01-12: A retrospective cohort study on the effect of adding adjuvant ovarian function suppression to endocrine therapy in premenopausal women with T1-T2 tumor hormone-positive breast cancer on survival and disease recurrence

Abstract Background: Breast cancer is the most common diagnosed cancer in women and is the leading cause of cancer death. Young women diagnosed with breast cancer are at higher rates of adverse outcomes in terms of survival and recurrence. Hormone sensitive breast cancer is the commonest subtype of breast cancer in this group. To date, the standard adjuvant treatment is endocrine therapy for both pre and post-menopausal women. Recent published studies have recommended adding ovarian function therapy to premenopausal women who are at high risk of recurrence. In this study we evaluated the impact of adding adjuvant ovarian function suppression for premenopausal women with small (T1 and T2) hormone receptor positive node negative breast cancer who did not receive any form of chemotherapy on overall survival and disease-free recurrence. Methods: We performed a retrospective study where we evaluated the electronic medical records of 4431 premenopausal women diagnosed with breast cancer in Asan Medical Center in Seoul, South Korea. All the analyzed patients were operated from the period of January 2006 till December 2019. The inclusion criteria were age of 55 and below, T1 and T2 tumors with N0 disease who received selective estrogen receptor modulators (SERM - Tamoxifen) and didn’t receive neo or adjuvant chemotherapy. We compared patients who received SERM (Tam Only) only to patients who received SERM and ovarian function suppression (Tam + OFS) medications. The primary endpoint was overall survival (OS), and the secondary endpoint was mortality and disease-free survival (DFS). We used chi-square test for categorical variables and t-test for continuous variables. The p-value was set as p&amp;lt; 0.05 as statistically significant. Kaplan Meier curve and log rank test were used to analyze the data for overall survival, disease-free survival and mortality. We performed an additional subgroup analysis adjusted to age, tumor size, Ki67%, progesterone receptor, HER2 status and type of operation. Results: There was equal distribution of cases between tamoxifen only group and tamoxifen + OFS group (2121 versus 2310 respectively). The median age in each group was 45 years of age. Tumor size of ≤0.5cm was the commonest in the tamoxifen only group whereas tamoxifen + OFS group had majority of cases with tumor size of 1 - 2cm. Both groups had a Ki-67% of 10-20%. Histologic grade of 2 and nuclear grade of 2 were most commonly representative in the comparing groups. Invasive ductal carcinoma was the most common histological subtype (93-94%) and invasive lobular carcinoma accounted for 5-6% of cases. Regarding immunohistochemistry results, 91-93% of patients were progesterone receptor positive and 68-73% were HER2 negative. The majority underwent breast conserving surgery compared to mastectomy. We have also looked at the pattern of prescribing OFS treatment in the Tamoxifen + OFS group regarding the length of treatment. Nearly 80% of patients received OFS treatment for a period of 1-2 years whereas only 5.2% received &amp;lt; 1 year and 1.8% &amp;gt;2years. After adjusting to age, tumor size, Ki67%, PR receptor and HER2 status, the result was only significant for higher risk of DFS in the TAM + OFS group in Ki67 &amp;lt; 20%. The OFS+TAM had more DFS and mortality events compared to TAM only group. However, the only significant result was the overall survival favoring tamoxifen only group with a p-value of 0.039 and HR of 1.05-7.99. Conclusion: Adding ovarian function suppression to tamoxifen in premenopausal hormone positive node negative T1-T2 tumors didn’t show any benefit in terms of disease-free interval and overall survival. Further studies are advised to assess the benefit of adding ovarian function suppression to this group of patients Table 1: baseline characteristics of Table 2: Disease Free Survival Subgroup Analysis Citation Format: Sarah Al Safi, Hee Jeong Kim, Seonok Kim, Sae Byul Lee, Jisun Kim, Tae-Kyung Yoo, Il-Yong Chung, Beom Seok Ko, Byung Ho Son. A retrospective cohort study on the effect of adding adjuvant ovarian function suppression to endocrine therapy in premenopausal women with T1-T2 tumor hormone-positive breast cancer on survival and disease recurrence [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 PO1-01-12.

Abstract PO4-16-11: De-escalation of anthracyclines during adjuvant therapy based on Oncotype RS: A single institution experience in Mexico City

Abstract Introduction: In Mexico, hormone positive HER2 negative breast cancer is the most frequent subtype, accounting for 76.6% of cases. For patients undergoing local control management through surgery; adjuvant chemotherapy is usually followed depending on different risk factors. In order to avoid overtreatment, different genomic firms have been approved aiding in a more objective decision. One of these genomic firms is the Oncotype Recurrence score. The TAILORx and RxPONDER trials have provided guidance in determining which patients are candidates for chemotherapy depending on their menopausal status. However, it has not yet been determined whether patients requiring chemotherapy can receive an anthracycline-free regimen. In the Plan B clinical trial, a non-inferiority analysis was conducted on early-stage breast cancer patients who received anthracycline-based or non-anthracycline-based chemotherapy, with the non-anthracycline regimen being non-inferior, including patients with a RS &amp;gt; 25. We intend to reevaluate these findings in our Mexican population. Methods: We evaluated 217 patients with early stage hormone sensitive HER2 negative breast cancer who had an Oncotype Recurrence score (RS) result. This retrospective cohort study took place by analyzing electronic records from January 2011 to December 2017 with patients treated at the National Cancer Institute in Mexico City. We included patients 18 years of age or older, any sex with an Oncotype RS ≥ 16 in premenopausal patients or ≥ 26 in postmenopausal patients who received adjuvant chemotherapy with or without anthracyclines. Our primary endpoint was iDFS comparing TC vs AC-T. Overall survival was set as a secondary endpoint. Results: Of the 217 patients with an Oncotype recurrence score, only 46 patients received adjuvant chemotherapy of which 71.7% were premenopausal with a median age of 45 years. Stage II was the most common stage with 91.3% of the population, as well as ductal carcinoma with 82.6%. All patients had positive lymph nodes, 54.3% at least 1 lymph node. Most patients received AC-T adjuvant chemotherapy (60.9%), and only 39.1% received TC. Of the 46 patients analyzed, only 19.6% (9) had a recurrence upon follow-up (Table 1). Median time of follow up was 87.5 months. Difference in Disease free survival could not be established between patients receiving AC-T with 105 months (CI 95% 94.36-117.43 months) vs TC with 94.09 months (CI 95% 83.85-104.34 months, &amp;lt; p.918) (Figure 1). Overall survival did not have a statistical difference between both chemotherapy regimens, p&amp;lt; 0.649 (Figure 2A), when comparing Oncotype RS, overall survival was better in those with Oncotype OS &amp;lt; 26, p&amp;lt; 0.023 (Figure 2B). Discusion As described previously in the Plan B trial, TC was non inferior to the conventional adjuvant regimen of AC-T in Hormone positive HER2 negative early-stage breast cancer. Our results tend to show similar results when compared to the Plan B. An important aspect to our study was that 71.7% of our patients were premenopausal, where in the Plan B trial only 35% were premenopausal, considered a higher risk group of patients. Although a statical difference couldn´t be established due to our small sample size, in DFS or OS when comparing the chemotherapy regimen. Premenopausal patients with an Oncotype RS &amp;lt; 26 could receive an anthracycline free regimen, without impact in their overall survival. Larger prospective studies are necessary to assure this conclusion. Figure 1 DFS (TC vs AC-T) Figure 2 A and B Overall Survival Table 1 (Baseline characteristics) Citation Format: Carlos Arturo González Núñez, Paula Cabrera-Galeana, Juan Enrique Bargalló Rocha, Rafael Vazquez-Romo, Sergio Aguilar-Villanueva, Alexandra Garcilazo, Areli Velazquez-Martinez, Andrea Maliachi, Ruben Rodriguez, Esmeralda Romero-Bañuelos. De-escalation of anthracyclines during adjuvant therapy based on Oncotype RS: A single institution experience in Mexico City [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 PO4-16-11.

Abstract PO2-19-04: Trial in Progress: The REJOIN Trial to Use Exercise and Education to Relieve Joint Pain in Older Breast Cancer Survivors Taking Aromatase Inhibitors

Abstract Background: Physical activity (PA) is a recommended part of breast cancer survivorship. PA promotes survival and mitigates symptoms in older breast cancer survivors (BCS), especially in reducing joint pain associated with Aromatase Inhibitors (AIs). The purpose of the study is to test if a self-management intervention (including education and exercise instruction) improve joint pain management better than standard care. Trial Design: This two-armed randomized controlled pilot trial (NCT03955627) includes insufficiently active BCS, 60 years and older, diagnosed with stage I-III hormone-sensitive breast cancer, who have completed primary cancer treatment and are within 6 months of initiating AIs. We adapted an evidence-based PA program for older adults (Fit and Strong!) that includes bi-weekly, supervised exercise sessions plus education (90 minutes total). The 16-week, evidence-based intervention program includes: 8-weeks of supervised sessions delivered remotely plus 8-weeks of self-guided home sessions with periodic phone coaching. We are conducting select geriatric assessments (e.g., cognitive assessment, polypharmacy) plus measurements of exercise (both self-reported and objectively measured by accelerometer), joint pain (brief pain inventory), and AI adherence (confirmed by self-report and prescription records) assessed four times (baseline, 4, 6 and 12 months). Eligibility Inclusion criteria: • Female, aged ≥ 60 years at enrollment • Planning to initiate (or are &amp;lt; 24 weeks from initiating) AIs • Diagnosed stages I-III breast cancer • ER+ tumor (at least 5% of cells) • Completed surgery, radiation and/or chemotherapy • Independent ambulator (verified by treating clinician/staff) • Physician approval to start an exercise program • Insufficiently active (less than 150 minutes per week of moderate intensity activity or less than two sessions per week of strength training) • Able to complete surveys and forms/understand English • Agree to random assignment to treatment or control group • Can commit to 8 weeks, bi-weekly classes offered by Zoom video and 8 Weeks of at-home exercise. • Must have internet access or data plan to support video conferencing software • Minimum cognitive impairment (verified by cognitive screening questions administered by phone) Specific Aims: The primary aim is to test the efficacy of a self-management intervention (exercise plus education) on AI-associated arthralgia. Hypothesis: Participants in the treatment group will report less pain than the control group. –A secondary aim is to test the effect of the pilot intervention on adherence to AIs. Hypothesis: Participants in the treatment group will report better AI Adherence than controls. Statistical Methods: We will use the Wilcoxon-Mann-Whitney t-test to assess the effect size from the start to the end of the trial, assuming a power calculation of 80%, a two-sided alpha of 10%, and a pooled standard deviation of one between the outcomes of the two groups (usual care and treatment) being compared. Present Accrual and Target Accrual REJOIN enrolled 12 participants in 2022, but two withdrew after randomization. We now have data on 10 participants with a target accrual of 24 overall. The original 12 were accrued at Penn State College of Medicine. We subsequently opened a second site at Wake Forest University and are recruiting the remaining participants. Contact information: For more information about REJOIN, please contact the study director, Dr. Shirley Bluethmann at sblueth@wakehealth.edu or the REJOIN project manager, Angela Grubb, at agrubb@wakehealth.edu Citation Format: Shirley Bluethmann, Peri Newman, Cristina Truica, Nancy Olsen, Heidi Klepin. Trial in Progress: The REJOIN Trial to Use Exercise and Education to Relieve Joint Pain in Older Breast Cancer Survivors Taking Aromatase Inhibitors [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 PO2-19-04.

The troglitazone derivative EP13 disrupts energy metabolism through respiratory chain complex I inhibition in breast cancer cells and potentiates the antiproliferative effect of glycolysis inhibitors

BackgroundThe metabolism of cancer cells generally differs from that of normal cells. Indeed, most cancer cells have a high rate of glycolysis, even at normal oxygen concentrations. These metabolic properties can potentially be exploited for therapeutic intervention. In this context, we have developed troglitazone derivatives to treat hormone-sensitive and triple-negative breast cancers, which currently lack therapeutic targets, have an aggressive phenotype, and often have a worse prognosis than other subtypes. Here, we studied the metabolic impact of the EP13 compound, a desulfured derivative of Δ2-troglitazone that we synthetized and is more potent than its parent compounds.MethodsEP13 was tested on two triple-negative breast cancer cell lines, MDA-MB-231 and Hs578T, and on the luminal cell line MCF-7. The oxygen consumption rate (OCR) of the treated cell lines, Hs578T mammospheres and isolated mitochondria was measured using the XFe24 Seahorse analyser. ROS production was quantified using the MitoSOX fluorescent probe. Glycolytic activity was evaluated through measurement of the extracellular acidification rate (ECAR), glucose consumption and lactate production in extracellular medium. The synergistic effect of EP13 with glycolysis inhibitors (oxamate and 2-deoxyglucose) on cell cytotoxicity was established using the Chou-Talalay method.ResultsAfter exposure to EP13, we observed a decrease in the mitochondrial oxygen consumption rate in MCF7, MDA-MB-231 and Hs578T cells. EP13 also modified the maximal OCR of Hs578T spheroids. EP13 reduced the OCR through inhibition of respiratory chain complex I. After 24 h, ATP levels in EP13-treated cells were not altered compared with those in untreated cells, suggesting compensation by glycolysis activity, as shown by the increase in ECAR, the glucose consumption and lactate production. Finally, we performed co-treatments with EP13 and glycolysis inhibitors (oxamate and 2-DG) and observed that EP13 potentiated their cytotoxic effects.ConclusionThis study demonstrates that EP13 inhibits OXPHOS in breast cancer cells and potentiates the effect of glycolysis inhibitors.

Abstract LB419: Neuroinflammation and aromatase inhibitor associated musculoskeletal syndrome (AIMSS) in breast cancer: Initial insights from [11C]PBR28 PET/MR imaging

Abstract Introduction: While 5-10 years of aromatase inhibitor (AI) treatment clearly improves survival rates of postmenopausal women with hormone-sensitive breast cancer, up to 85% of AI users report aromatase inhibitor associated musculoskeletal syndrome (AIMSS, including arthralgias, myalgias, and muscle stiffness). The biological mechanisms underlying AIMSS are not well understood, but accumulating preclinical and clinical evidence implicate an important role for neuroinflammation in the development and maintenance of other types of chronic musculoskeletal pain (e.g., low back pain, fibromyalgia etc.). The purpose of this pilot study was to investigate the role of neuroinflammation in breast cancer patients with AIMSS. Methods: This cross-sectional case control study used Siemens 3 T integrated positron emission tomography-magnetic resonance imaging (PET/MRI) with the radioligand [11C]PBR28, which binds to the neuroinflammation marker 18kDa translocator protein (TSPO), to assess neuroinflammation in two cohorts (chronic AIMSS, no-AIMSS) of breast cancer patients undergoing AI therapy, and age-, sex- and TSPO genotype-matched healthy controls. Static [11C]PBR28 PET images were reconstructed from 60-90 minutes post-injection. Standardized uptake value (SUV) maps were obtained voxel-wise by normalizing radioactivity by injected dose/body weight. SUV maps were normalized to whole brain to obtain SUV ratio (SUVR) maps. SUVR images spatially normalized to MNI template and then spatially smoothed (FWHM=8mm). Results: Two breast cancer patients (1 AIMSS, 1 no-AIMSS) and 2 matched healthy controls were included in this analysis. Compared to their individual matched healthy controls, both breast cancer patients showed increased [11C]PBR28 signal uptake in the thalamus/midbrain and pons. This elevated signal was more prominent in the breast cancer patient with AIMSS. Conclusions: These preliminary findings suggest an elevated signal of neuroinflammation in the thalamus and brainstem in AI-treatment and AIMSS, aligning with existing literature emphasizing their pivotal role in chronic pain pathology. While it is imperative to acknowledge the limitation of a small sample size, these promising findings suggest a potential role of neuroinflammation for the first time in AIMSS. Future focused Region of Interest (ROI) analysis in thalamus and brainstem with a larger sample size may confirm. Citation Format: Yehui Zhu, Natalie Swanson, Jennifer Murphy, Minhae Kim, Ann Partridge, Robert Edwards, Kristin Schreiber, Marco Loggia. Neuroinflammation and aromatase inhibitor associated musculoskeletal syndrome (AIMSS) in breast cancer: Initial insights from [11C]PBR28 PET/MR imaging [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB419.

Abstract 4975: Stretching the boundary of Oncotype DX testing

Abstract Background: The predictive value of Oncotype DX in early-stage breast cancer had been well established. Strongest data support the use of chemotherapy for Recurrence Score (RS) &amp;gt; 30, with 25-30 deriving some benefit. Those with intermediate RS 16-25 are thought to have a small benefit from chemotherapy, especially premenopausal patients. Tumor size &amp;gt;5 cm is viewed as a high-risk feature regardless of RS. Our goal is to investigate how patients with uncertainty regarding their anticipated recurrence risk were managed at our institution. Methods: We conducted a retrospective analysis to explore the management of non-metastatic HER-2 negative hormone sensitive breast cancer patients diagnosed between 01/2018 &amp;12/2020 stratifying them into the following study groups of interest: premenopausal (age &amp;lt;50), RS 16-25 compared to RS 26-30 and tumor size &amp;gt;5cm. Patients were compared based on whether they received adjuvant chemotherapy or not. The primary endpoint was the rate of local recurrence. Results: The results of our analysis are illustrated in the table. Studying the premenopausal group, 91.3% had RS &amp;lt; 16; yet 35% of them received chemotherapy. Patients with RS &amp;gt; 25 represented 3.2% of the premenopausal group, 12.5% of which did not receive chemotherapy. The six recurrences in the premenopausal group were all from the RS &amp;lt;16 subgroup. Comparing the RS 26-30 to the RS 16-25 group, patients were on average older with tumors being on average smaller, yet more patients were treated with chemotherapy; and there were no recurrences noted in both subgroups. Finally, in the tumor size &amp;gt;5 cm group, 91.4% had RS &amp;lt;16, almost all were premenopausal with many patients being lymph node negative, yet more than half received chemotherapy. Conclusions: In our study we demonstrate that in certain subgroups of early-stage breast cancer there is inconsistency in clinical practice when prescribing chemotherapy to patients factoring in their Oncotype DX scores. There is need for larger trials to guide clinicians on using Oncotype DX in those subgroups of patients. Characteristics, Treatment Pattern and Outcomes of Patient Groups of Interest Characteristics Premenopausal (N=506) RS 16-25 (N=28) RS 26-30 (N=36) Tumor Size &amp;gt;5 cm (N=47) Age, Mean (SD) 42.65 (5.46) 44.71 (3.85) 63.56 (9.65) 42.02 (6.14) Age, Range 19 - 49 36 - 49 45 - 79 28 - 57 Mean Tumor Size, mm (SD) 29.66 (52.21) 29.57 (33.88) 16.88 (11.19) 83.61 (37.52) Lymph Nodes Positive, n (%) 91 (18.0%) 2 (7.1%) 0 (0.0%) 16 (34.0%) Received Chemotherapy, n (%) 184 (36.4%) 7 (25.0%) 13 (36.1%) 25 (53.2%) Local Recurrence, n (%) 6 (1.2%) 0 (0.0%) 0 (0.0%) 0 (0.0%) Mean Follow- Up, months (SD) 19.28 (8.20) 19.39 (7.07) 21.21 (11.04) 19.26 (8.93) Citation Format: Zaid Al-Saheli, Vrushali Dabak. Stretching the boundary of Oncotype DX testing [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4975.

Tamoxifen in breast cancer and risk of Parkinson's disease: A meta-analysis

BackgroundTamoxifen is widely used for hormone-sensitive breast cancer, achieved by modulating the estrogen receptor activity in a tissue-specific manner. There is evidence to support the protective effects of estrogen against Parkinson's disease (PD), a common neurodegenerative condition. Some epidemiologic studies suggest the use of tamoxifen may modulate the PD risk. We conducted a meta-analysis to examine the association between tamoxifen and risk of PD. MethodsA search of PubMed using search terms synonymous with “tamoxifen” and “Parkinson's disease” was conducted. Outcomes of interest were the odds ratio (OR) of PD comparing tamoxifen-exposed to -unexposed women, as well as the incidence rate of PD in tamoxifen-exposed women. ResultsA total of 37,932 subjects with breast cancer, comprising 17,233 tamoxifen-exposed subjects and 20,699 tamoxifen-unexposed subjects, satisfied the inclusion criteria. The exposure to tamoxifen ranged from 30-96 months. Using the common-effect model, the pooled OR of PD was 2.4, with (95% CI 1.91-3.01, P < 0.0001), with high heterogeneity (I2 = 81.5%, Cochran's Q test P = 0.001). Pooling 28,640 tamoxifen-exposed patients under the common-effect model found an incidence rate of 5.86 events per 10,000 person-years (95% CI 4.82–7.12) with minimal heterogeneity (I2 = 26%, Cochran's Q test P = 0.258). ConclusionsOur meta-analysis suggests that tamoxifen use may be associated with an increased PD risk in women. However, due to heterogeneity and potential limitations of some of the studies, further clinical and functional validation will be needed. Longitudinal studies supported by imaging and biomarkers evaluation will be useful to identify the mechanisms linking tamoxifen and PD risk.