Hormone-sensitive Breast Cancer Research Articles

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< 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 < 1 year and 1.8% >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 < 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 > 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, < p.918) (Figure 1). Overall survival did not have a statistical difference between both chemotherapy regimens, p< 0.649 (Figure 2A), when comparing Oncotype RS, overall survival was better in those with Oncotype OS < 26, p< 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 < 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 < 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) > 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 >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 &12/2020 stratifying them into the following study groups of interest: premenopausal (age <50), RS 16-25 compared to RS 26-30 and tumor size >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 < 16; yet 35% of them received chemotherapy. Patients with RS > 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 <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 >5 cm group, 91.4% had RS <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 >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.

SAT621 Hemorrhage After Treatment: A Case Of Pituitary Apoplexy In Metastatic Prostate Cancer After Leuprolide

Abstract Disclosure: M. Dillon: None. S. Shteyman: None. W. Rashid: None. B.P. Ramchandani: None. A.G. Samat: None. Introduction: Hormone-sensitive cancers, including prostate and breast cancer, and some gynecological conditions can be treated with GnRH agonists, including leuprolide. However, pituitary apoplexy is a rare potential complication after administration. Case Description: 71-year-old gentleman with metastatic hormone-sensitive prostate cancer presented with an acute headache after receiving a dose of leuprolide. This was his first GnRH agonist dose after prior Degarelix treatment. After two hours, the patient developed a constant throbbing headache, palpitations, left eye tearing and non-bilious non-bloody vomiting. Vitals were within normal ranges, and initial lab work showed low serum cortisol of 4.6. CT scan of the head showed exophthalmos and a mildly enlarged sella. Subsequent MRI demonstrated pituitary hemorrhage and optic chiasm impingement from resulting swelling. Hormone levels remained normal. Since the patient did not develop visual field defects or other ocular complaints, the decision was to manage the patient medically rather than with surgery. The day after admission, he developed hypotension requiring high dose steroids. After discharge, outpatient repeat MRI showed interval resolution of hemorrhage into a predominantly cystic pituitary macroadenoma. Discussion: With continued stimulation, GnRH agonists desensitize the pituitary and cause a downregulation of hormonal induced cancer growth. However, there is an initial transient burst of stimulation that can induce pituitary apoplexy in patients who already have a large adenoma. The hemorrhage and subsequent swelling cause a sudden severe headache and possible visual loss or hypopituitarism. This is life-threatening due to hypotension from catecholamine insensitive blood vessels in the absence of cortisol. Treatment involves high dose steroids, frequent sodium checks and possible emergency neurosurgery for decompression. It is important with GnRH agonists to watch out for this rare complication, whether the hormonal axis is being suppressed for metastatic cancer treatment or for hormonally driven gynecological conditions. Sources: Briet C, Salenave S, Bonneville JF, Laws ER, Chanson P. Pituitary Apoplexy. Endocr Rev. 2015 Dec;36(6):622-45. doi: 10.1210/er.2015-1042. Epub 2015 Sep 28. PMID: 26414232. Tanios G, Mungo NA, Kapila A, Bajaj K. Pituitary apoplexy: a rare complication of leuprolide therapy in prostate cancer treatment. BMJ Case Rep. 2017 Jul 14; 2017:bcr2016218514. doi: 10.1136/bcr-2016-218514. PMID: 28710301; PMCID: PMC5534692. Presentation: Saturday, June 17, 2023

Генотипы CYP2D6*3, *4, *6 и гипертрофия эндометрия у больных раком молочной железы на фоне терапии тамоксифеном

Tamoxifen therapy results in endometrial thickening in some patients with hormone-sensitive breast cancer (HSBC). The data on the impact of polymorphic variants of the CYP2D6 gene encoding the CYP2D6 enzyme of the cytochrome P450 family on the efficacy and safety of treatment with tamoxifen are controversial. A prospective cohort study was aimed to explore the association of CYP2D6*3, *4, *6 polymorphisms with the risk of endometrial thickness during adjuvant tamoxifen therapy for HSBC. A total of 145 patients with resectable HSBC, who received 20 mg of oral tamoxifen per day, were enrolled. The CYP2D6*3, *4, *6 polymorphisms were identified by real-time PCR. Endometrial thickness was measured by ultrasonography after 3, 6 and 9 months of endocrine therapy. The study showed that endometrial hyportrophy was more often found in patients having no alternative alleles after 3 months of follow-up (40% against 23.2% in the group of “poor” metabolizers; p = 0.034). Meta-analysis of all follow-up periods has revealed that “normal” metabolizers show a significantly higher rate of endometrial thickness than “poor” metabolizers (OR = 1.88; 95% CI = 1.27–2.79; p = 0.002). A lack of significant differences in indicators of the state of endometrium between groups of patients with different CYD2D6 genotypes and menopausal status requires further investigation.

The role of CDK4/6 inhibitors in older and younger patients with breast cancer: A systematic review and meta-analysis.

Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors have an extremely important impact on the treatment of hormone-sensitive breast cancer (BC) and have radically changed the first-line treatment for metastatic disease with increased rates of treatment response, overall survival (OS), and progression-free survival (PFS). We performed a pooled analysis of randomized trials to validate or refute the hypothesis that there is a significant survival benefit of adding anti-CDK4/6 inhibitors to standard endocrine therapy (ET) in older patients with advanced BC. We selected only English-language phase II/III randomized controlled trials that compared ET alone with ET with anti-CDK4/6 inhibitors in the treatment of advanced BC, with subgroups reporting the outcomes of elderly patients (usually at least 65 years). The primary endpoint was OS. The review process led to the inclusion of 12 articles and two meeting abstracts, including a total of 10 trials. The addition of CDK4/6 inhibitors to ET (letrozole or fulvestrant) significantly reduced mortality risk by 20% in younger patients (fixed-effect model; HR 0.80; 95% CI 0.72-0.9; p<0.01) and 21% in older BC patients (HR 0.79; 95% CI 0.69-0.91; p<0.01). No OS data were available for patients ≥70 years. This large, pooled analysis is the first to demonstrate that CDK4/6 inhibitors confer OS and PFS benefits in elderly patients (those aged ≥65 years) with advanced ER+BC and to indicate that it should be discussed with and offered to all patients after geriatric assessment and according to the toxicity profile.

Investigation of the combined cytotoxicity induced by sodium butyrate and a flavonoid quercetin treatment on MCF-7 breast cancer cells

ABSTRACT Quercetin (QUE) belonging to the flavonoid class is a common phytochemical present in the daily diet of some individuals. Quercetin is an important source of free radical scavengers. This property makes this flavonoid a reliable antioxidant with the following properties: anti-inflammatory, anti-diabetic, antimicrobial and anti-carcinogenic. Sodium butyrate (NaBu) acts as a histone deacetylase inhibitor (HDACi) and is known to regulate apoptosis in cancer cells. Combining natural flavonoids such as QUE with different substances may synergistically enhance their anti-carcinogenic capacity. Thus, the aim of this study was to examine the combined treatment effects of QUE and NaBu in hormone-sensitive breast cancer cells in vitro. MCF-7 breast cancer cells were treated with QUE alone, NaBu alone, as well as QUE and NaBu combined to determine the following: cell proliferation, levels of protein annexin A5 (ANXA5) and reactive oxygen species (ROS), mRNA protein expression, as well as cell and nuclear morphology. Data demonstrated that either QUE or NaBu alone inhibited cell proliferation, and reduced levels protein ANXA5, ROS and mRNA protein expression, The combination of QUE and NaBu produced a significant synergistic inhibitory effect compared to treatment groups of QUE or NaBu alone. In conclusion, our findings showed that the combination treatment of QUE and NaBu may constitute a promising therapeutic approach to breast cancer treatment but this needs further molecular and in vivo investigations

Validation of liquid biopsy for ESR1-mutation analysis in hormone-sensitive breast cancer: a pooled meta-analysis.

Several retrospective and prospective studies have shown that genomic alterations in Estrogen-receptor one (ESR1) can be characterized not only in tissue samples but also by sequencing circulating tumor DNA (ctDNA) in liquid biopsy. Therefore, liquid biopsy is a potential noninvasive surrogate for tissue biopsy. This meta-analysis was designed to compare the prevalence of ESR 1 mutation detected with liquid biopsy and tissue biopsy. A pooled meta-analysis of studies published between 1 January 2007 and 1 March 2021 was conducted regarding the methodologies used for ESR1 mutation analysis. Liquid biopsy is a valid, inexpensive, and attractive noninvasive alternative to tumor biopsies for the identification of ESR1 mutations. Liquid biopsy for ESR 1 analysis would facilitate regular testing, allowing monitoring of the sensitivity to ET and guiding treatment strategies.

P-677 Letrozole inhibits ovulation via reducing responsiveness to luteinizing hormone in in vitro-grown mouse follicles

Abstract Study question Does letrozole reduce responsiveness to luteinizing hormone (LH) in in vitro-grown mouse follicles? Summary answer We found that letrozole reduced responsiveness to LH via reducing of luteinizing hormone/chorionic gonadotropin receptor (Lhcgr) transcription in in vitro. What is known already The continuous dosing of letrozole, the third-generation aromatase inhibitor, is used for the controlled ovarian stimulation (COS) of fertility preservation cycles in women with hormone-sensitive breast cancer to prevent the transient rise of serum estrogen levels. Recently, lower oocyte maturation rates and higher abnormal fertilization rates in COS with letrozole compared to standard COS have been reported. The studies using aromatase knockout mice and estrogen receptor beta knockout mice showed that intra-follicular estrogen is essential for responsiveness to LH of granulosa cells. However, whether letrozole reduces responsiveness to LH of follicles remains unknown. Study design, size, duration We evaluated the effect of letrozole on responsiveness to LH using in vitro mouse follicle culture system. Preantral follicles (150-200 µm) with a small number of stromal cells were isolated from 3 weeks old C57BL/6jjcl mouse ovaries and cultured in the presence of letrozole. We analyzed in vitro ovulation ability, and expression levels of ovulation-related genes to clarify the effect of letrozole on responsiveness to LH of follicles. Participants/materials, setting, methods The follicles were cultured with letrozole (0.01µM, 0.1µM, or 1µM) or vehicle (0.1% DMSO) for 5 days followed by 5 IU/ml hCG and 5 ng/ml hEGF stimulation as ovulation induction. The diameter and survival rate of follicles were assessed. After16 hours after ovulation induction, we assessed the ovulation and measured the transcription of Lhcgr, Ptgs2, Runx1 and Actb (internal control) in the follicles by RT-qPCR. We conducted a collateral experiment in the presence of estradiol. Main results and the role of chance The follicle growth and survival rate did not change by letrozole in vitro. However, in vitro ovulation was reduced by the addition of letrozole in a dose-dependent manner (Cochran-Armitage trend test, P &amp;lt; 0.0001): 41.2% in the 0.01µM letrozole treated group (n = 23), 10.5% in the 0.1µM letrozole treated-group (n = 17), and no ovulation in the 1µM letrozole treated-group (n = 19) compared with 69.6% in the vehicle-group (n = 18). Exogenous estrogen addition restored the ovulation ability of 1µM letrozole-treated follicle to the same levels as the vehicle group. RT-qPCR revealed that 0.1 µM letrozole significantly reduce the transcription levels of Lhcgr (P = 0.0027), Runx1 (P = 0.0124), and Ptgs2 (P = 0.0067) compared with vehicle-treated follicles. Exogenous estrogen addition restored the transcription of these genes to levels observed in vehicle-treated follicles. We also observed a positive correlation between the transcription of Lhcgr and Ptgs2 (R = 0.55, P = 0.0003), Lhcgr and Runx1 (R = 0.71, P &amp;lt; 0.0001), and Ptgs2 and Runx1 (R = 0.77, P &amp;lt; 0.0001). Our results suggested that letrozole-treated follicles impaired ovulation due to dysregulation of Lhcgr transcription and its downstream cascade caused by estrogen deficiency. Limitations, reasons for caution This is an in vitro experiment using a mouse model. Further research is needed to determine whether our findings are applicable to humans. Wider implications of the findings Our findings imply that letrozole may have disadvantages in not only ovulation, but also subsequent reproductive processes affected by the effectiveness of the LH surge, such as oocyte maturation, fertilization, and preimplantation embryo development. When evaluating oocyte cryopreservation for fertility preservation, it may be necessary to consider the COS protocol. Trial registration number Not applicable

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 .

Part II: Interactive case: Drug‐induced endocrine disorders

Part <scp>II</scp>: Interactive case: <scp>Drug‐induced</scp> endocrine disorders

Prognostic and clinical impact of the endocrine resistance/sensitivity classification according to international consensus guidelines for advanced breast cancer: an individual patient-level analysis from the Mammella InterGruppo (MIG) and Gruppo Italiano Mammella (GIM) studies

Prior exposure to adjuvant endocrine therapy (ET) and timing to recurrence are crucial factors for first-line treatment choices in patients with hormone receptor-positive/HER2-negative (HR+/HER2-) breast cancer (BC) and in clinical trial eligibility, classifying metastatic HR+/HER2- BC as endocrine sensitive (ES) or primary (1ER)/secondary (2ER) resistant. However, this classification is largely based on expert opinion and no proper evidence exists to date to support its possible prognostic and clinical impact. This analysis included individual patient-level data from 4 adjuvant phase III randomized trials by the Mammella InterGruppo (MIG) and Gruppo Italiano Mammella (GIM) study groups. The impact of endocrine resistance/sensitivity classification on overall survival (mOS, defined as time between date of distant relapse and death) was assessed in both univariate and multivariate Cox proportional hazards models. Between November 1992 and July 2012, 9058 patients were randomized in 4 trials, of whom 6612 had HR+/HER2- BC. Median follow-up was 9.1 years (interquartile range [IQR] 5.6-15.0). In the whole cohort, disease-free survival and OS were 90.4% and 96.6% at 5 years, and 79.1% and 89.4% at 10 years, respectively. The estimated hazard of recurrence raised constantly during the first 15 years from diagnosis, being more pronounced during the first 2 years and less pronounced after year 7. Among the 493 patients with a distant relapse as first disease-free survival event and available date on ET completion, 72 (14.6%), 207 (42.0%) and 214 (43.4%) were classified as having 1ER, 2ER and ES, respectively. Median follow-up from diagnosis of a distant relapse was 3.8 years (IQR 1.6-7.5). Patients with 1ER were significantly more likely to be younger, to have N2/N3 nodal status, grade 3 tumours and to develop visceral metastases. Site of first distant relapse was significantly different between the 3 groups (p=0.005). In patients with 1ER, 2ER and ES breast cancer, median mOS was 27.2, 38.4 and 43.2 months, respectively (p=0.03). As compared to patients with ES disease, a higher risk of death was observed in those with 1ER (adjusted Hazard Ratio [aHR] 1.54; 95% CI 1.03-2.30) and 2ER (aHR 1.17; 95% CI 0.87-1.56) (p=0.11). This large analysis with long-term follow-up provides evidence on the prognostic and clinical impact of the currently adopted endocrine resistance/sensitivity classification in patients with HR+/HER2- advanced BC. This classification may be considered a valid tool to guide clinical decision-making and to design future ET trials in the metastatic setting. AIRC.

Aromatase inhibition plus/minus Src inhibitor saracatinib (AZD0530) in advanced breast cancer therapy (ARISTACAT): a randomised phase II study

PurposeThe development of oestrogen resistance is a major challenge in managing hormone-sensitive metastatic breast cancer. Saracatinib (AZD0530), an oral Src kinase inhibitor, prevents oestrogen resistance in animal models and reduces osteoclast activity. We aimed to evaluate the efficacy of saracatinib addition to aromatase inhibitors (AI) in patients with hormone receptor-positive metastatic breast cancer.MethodsThis phase II multicentre double-blinded randomised trial allocated post-menopausal women to AI with either saracatinib or placebo (1:1 ratio). Patients were stratified into an “AI-sensitive/naïve” group who received anastrozole and “prior-AI” group who received exemestane. Primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), objective response rate (ORR) and toxicity.Results140 patients were randomised from 20 UK centres to saracatinib/AI (n = 69) or placebo/AI (n = 71). Saracatinib was not associated with an improved PFS (3.7 months v. 5.6 months placebo/AI) and did not reduce likelihood of bony progression. There was no benefit in OS or ORR. Effects were consistent in “AI-sensitive/naive” and “prior-AI” sub-groups. Saracatinib was well tolerated with dose reductions in 16% and the main side effects were gastrointestinal, hypophosphatemia and rash.ConclusionSaracatinib did not improve outcomes in post-menopausal women with metastatic breast cancer. There was no observed beneficial effect on bone metastases.CRUKE/11/023, ISRCTN23804370.