Endocrine Treatment Research Articles

How overall survival is conditioned in the progression to treatment with cyclin inhibitors plus endocrine treatment in metastatic breast cancer with luminal phenotype.

e13079 Background: CDK4/6 inhibitors plus endocrinotherapy (ET) is the standard first-line treatment for metastatic breast cancer with a luminal phenotype. However, the response to this treatment is highly dependent on its previous efficacy. Methods: We analyzed the overall survival in a cohort of 127 patients with metastatic luminal breast cancer in progression after treatment with CDK4/6 inhibitors plus ET. Results: The median age of the group was 67 years (41-96), the interval time between initial diagnosis and first recurrence was 0 in 41 (32%), 1-60 months in 37 (29%) and more than 60 months in 39 (38%). The first line in the metastatic setting was CDK4/6 plus ET in 81 patients (64%), ET in 15 (12%) and 31 (24%) were treated with chemotherapy. The status of HER2 expression was HER2 low in 77% and 43 % had visceral metastases disease. The median progression-free survival for the patients treated with CDK4/6 inhibitors plus ET was 9 months, with a total of deaths of 69 (55%). Overall survival after progression on CDK4/6 plus ET was 38 months (28 – 47) and the most important factor for overall survival was the response time to treatment with CDK4/6 inhibitors plus ET. Conclusions: The most important factor for overall survival is the duration of treatment with CDK4/6 inhibitors plus ET. Patients with a response time of less than 6 months had a median overall survival after progression of 11 months (3 – 19), while the 6- to 12-month group had a median of 39 months (19 – 59) and the group with more than 12 months had the best prognosis with a median overall survival of 53 months (37 – 68). We need to improve the new treatment options for patients who respond for less than 6 months to treatment with CDK4/6 plus ET.

Enfortumab vedotin (EV) in triple-negative breast cancer (TNBC) and HR+/HER2- breast cancer (BC) cohorts of EV-202.

1005 Background: EV, a Nectin-4–directed antibody–drug conjugate, is approved for use in urothelial cancer. Nectin-4 is expressed in several solid tumors, including BC. EV monotherapy was evaluated in TNBC and HR+/HER2- BC in EV-202 (NCT04225117). Methods: In this open-label, multicohort, phase 2 trial, eligible adults had locally advanced or metastatic (la/m) solid tumors, measurable disease, and ECOG PS 0–1. In BC cohorts, patients (pts) had prior taxanes or anthracyclines, ≥1 standard-of-care cytotoxic regimen and ≤2 lines (L) of cytotoxic therapy for la/mBC, and prior PD-1/L1 inhibitor (TNBC) or endocrine treatment (tx) with a CDK4/6 inhibitor (HR+/HER2- BC). Nectin-4 expression was not required but was assessed retrospectively. Pts received EV 1.25 mg/kg intravenously days 1, 8, and 15 of each 28-d cycle until discontinuation criteria (eg, disease progression, unacceptable toxicity) were met. Primary endpoint was confirmed objective response rate (ORR); ≥10 (TNBC) or ≥12 (HR+/HER2- BC) responders out of 40 evaluable pts were needed to claim promising antitumor activity. Secondary endpoints were duration of response (DOR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety/tolerability. Antitumor activity was investigator-assessed per RECIST v1.1. Results: In the TNBC cohort, 42 female pts received EV as of Mar 3, 2023 (median follow-up, 11.8 mo). Median age was 53 y, 64% had ≥2L systemic tx for metastatic BC, and 33% had prior sacituzumab govitecan. ORR was 19.0%. Grade ≥3 tx-related adverse events (TRAEs) in >1 pt were decreased neutrophil count (n=3, 7%), decreased white blood cell count (n=2, 5%), and increased aspartate aminotransferase (n=2, 5%). Selected TRAEs of special interest were skin reactions (n=25, 60%), peripheral neuropathy (n=11, 26%), and hyperglycemia (n=2, 5%). In the HR+/HER2- BC cohort (median age, 57.0 y), 45 female pts received EV as of Dec 3, 2022 (median follow-up, 11.2 mo). Most (73%) had ≥3L systemic tx for metastatic BC. ORR was 15.6%. Grade ≥3 TRAEs in >1 pt were maculopapular rash (n=7, 16%), pruritus and increased aspartate aminotransferase (both n=3, 7%), and abdominal pain and erythema (both n=2, 4%). Selected TRAEs of special interest were skin reactions (n=28, 62%), peripheral neuropathy (n=12, 27%), and hyperglycemia (n=5, 11%). Additional efficacy data for both cohorts are in the table. Conclusions: EV showed antitumor activity in heavily pretreated TNBC. Safety in both cohorts was manageable and consistent with previous reports. Clinical trial information: NCT04225117 . [Table: see text]

Association between PIK3CA mutations and disease-free survival in patients with HR+, HER2- tumors treated with adjuvant hormonal therapy: A real-world study in Croatia.

e12512 Background: Disease recurrence of early hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) breast tumor subtype is particularly challenging to manage due to its complex and very heterogeneous biological nature. Namely, due to primary and secondary resistance, one-quarter of patients with early disease will present with the disease recurrence. This variability in the timing of recurrence highlights the need to better identify key biomarkers that could predict therapeutic outcomes and guide personalized treatment strategies for these patients. Mutations in the phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) gene have a high prevalence of 30% to 40% in HR+/HER2- advanced breast cancer. They lead to activation of the PI3K/AKT/mTOR pathway, promoting cell growth, and proliferation, and are associated with poor prognosis in advanced breast cancer. Our aim was to examine this association and impact of PIK3CA mutation status on disease free survival (DFS) in HR+/ HER2- early breast cancer patients. Methods: We conducted a multicentric, retrospective cohort study in five Croatian institutions from July 2020 to December 2021. Study included initially early HR+/HER2- breast cancer patients who have been diagnosed with disease recurrence during adjuvant hormonal treatment or within first six years of follow up. The Cobas PIK3CA Mutation Testing Kit was used for real-time PCR-based amplification and mutation detection on the Cobas z 480 analyzer. We have analyzed differences in DFS from initiation of adjuvant endocrine therapy, using Cox, proportional hazard regression. Results: There was total of 186 patients, out of which 40.9% tested positive for the PIK3CA mutation. Primary and adjuvant treatment and in particular adjuvant endocrine treatment was similar between the two groups. After adjustment for 14 relevant covariates, we found that patients with positive PIK3CA status and with H1047 PIK3CA mutation had significantly lower hazard for disease recurrence in comparison to patients with no PIK3CA mutation (HR 0.65; 95% CI 0.45; 0.95; p = 0.024; HR 6.52; 95% CI 1.15; 36.95; p = 0.034 respectively; false discovery rate, FDR < 10%) and higher odds for late recurrence (p = 0.001, FDR < 5%). Conclusions: This study highlights the potential impact of PIK3CA mutations on disease recurrence during/following adjuvant endocrine treatment and by that potentially opens the door for further investigation of possibly more personalized treatment strategies.

Favorable outcome of neoadjuvant endocrine treatment than surgery-first in female HR-positive/HER2-negative breast cancer patients-A NCDB analysis (2010-2016).

To assess the efficacy of neoadjuvant endocrine therapy in female HR-positive/HER2-negative breast cancer patients. We identified female patients aged ≥18 years with cT1-4N0-XM0, HR(+), and HER2(-) breast cancer from the National Cancer Database. The patients who underwent surgery first were categorized as "surgery-first," while those who received NET before surgery were classified as "NET." Propensity score-matching, Cox proportional-hazard model, variance inflation factors, and interaction analysis were employed to estimate the correlation between NET and survival outcomes. Among 432,387 cases, 2914 NET patients and 2914 surgery-first patients were matched. Compared with the surgery-first group, the NET group received less adjuvant chemotherapy (p < 0.001). Furthermore, the NET group exhibited higher survival probabilities compared with the surgery-first group (3 years: 91.4% vs. 82.1%; 5 years: 82.1% vs. 66.8%). Multivariate Cox analysis indicated that NET was associated with improved OS (surgery-first vs. NET: HR 2.17, 95% CI: 1.93-2.44). Age over 55 years old, having public insurance, higher CDCC score, higher NSBR grade, ER(+)PR(-), and advanced clinical stage were related to worse OS (all p < 0.05). There was an interaction between age, race, income, and home and treatment regimen (all p < 0.05). NET may be a more effective treatment procedure than surgery-first in female HR-positive/HER2-negative, non-metastatic breast cancer patients. Future clinical studies with more detailed data will provide higher-level evidence-based data.

Efficacy and safety of eribulin plus gemcitabine in second-line or beyond for patients with HER2-negative metastatic breast cancer (MBC): A multicenter, open-label, single-arm, phase II study.

e13139 Background: The combination of eribulin and gemcitabine has demonstrated a similar progression-free survival (PFS) benefit as paclitaxel plus gemcitabine, with less neurotoxicity, for patients with MBC who have not received prior cytotoxic chemotherapy. However, the effect of eribulin plus gemcitabine on PFS in second line or beyond remains unclear. Methods: This open-label, single-arm, phase II study (NCT05263882) was conducted at 14 institutions in China. Eligible patients had histologically confirmed HER2-negative MBC and had received at least one prior taxane-containing chemotherapy regimen for advanced disease, and anthracycline-containing regimens in the adjuvant setting. Patients received intravenous infusions of eribulin (1.4 mg/m2) and gemcitabine (1.0 g/m2) on days 1 and 8 of a 21-day cycle. Efficacy outcomes, including PFS, objective response rate (ORR), and disease control rate (DCR), were assessed using RECIST v1.1. Adverse events (AEs) were graded according to NCI-CTC version 5.0. Results: A total of 70 patients were enrolled from November 2021 to October 2023; 47 (71.4%) had HR+HER2- and 18 (28.6%) had triple-negative MBC. The median patient age was 50 years (range: 31-68), and the sites of metastasis were the bone (68.6%), liver (52.9%), lymph nodes (48.6%), lung (44.3%) and brain (10.0%). Patients had received a median of 3 prior lines of systemic treatment, 2 lines of chemotherapy, and 1 line of endocrine treatment. Among all patients, the ORR was 48.6%, the DCR was 92.9% and the median PFS was 7.2 months. For the HR-positive subgroup, the median PFS was 8.4 months, while for the triple-negative subgroup, it was 6.3 months. Among HR+ patients who had received prior CDK4/6 inhibitor treatment, the median PFS was 7.2 months. In the subgroup of HR+ patients who had not received CDK4/6 inhibitor treatment, the median PFS had not been reached. For the HR+ HER2-low subgroup, the median PFS was 8.4 months. The most common grade 3-4 AEs were hematological, including neutropenia (38.6%), leukopenia (31.4%), anemia (24.3%), and thrombocytopenia (15.7%). Grade ≥3 perceived AEs were relatively low. Conclusions: Eribulin plus gemcitabine was effective in heavily pretreated patients with HER2- MBC, while maintaining a predictable and manageable safety profile. Clinical trial information: NCT05263882 . [Table: see text]

Preliminary results from a phase 1 study of AC699, an orally bioavailable chimeric estrogen receptor degrader, in patients with advanced or metastatic breast cancer.

3074 Background: Endocrine therapy is a critical component of treatment for over 200,000 patients diagnosed yearly with estrogen receptor positive (ER+)/HER2- breast cancer. Although selective ER degraders (SERDs) have improved progression-free survival in this patient population, as monotherapy they have shown very limited overall response rates (ORR). AC699 is a novel chimeric degrader that binds, ubiquitinates and degrades ERα by bringing it into close proximity with an E3 ligase. This mechanism of action may result in greater specificity and more complete target blockade compared to SERDs. Initial results from the ongoing first-in-human dose escalation study of AC699 (NCT05654532) are presented here. Methods: The study employed a 3+3 design, with the option of adding backfill patients to each cohort cleared and deemed safe. Patients must have had locally advanced or metastatic ER+/HER2- breast cancer and received at least 2 prior lines of endocrine treatment, or at least 1 prior line if combined with a CDK4/6 inhibitor. AC699 was administered orally once daily in 28-day cycles. Tumor responses were assessed every 2 cycles using RECIST v1.1 criteria. The relationship between ESR1 mutational status and anti-tumor activity was investigated as an exploratory analysis. Results: A total of 22 patients had received AC699 in 3 dose cohorts (100, 200 and 300 mg) at the time of data cutoff. The median age was 61 years and the median lines of prior therapy was 5 (range 2-10). Prior treatments included CDK4/6 inhibitor (100%), aromatase inhibitor (91%), fulvestrant (82%), novel oral SERD or covalent antagonist (SERCA) (23%), and ER chimeric degrader (14%). Eighteen patients had measurable disease while 4 had bone lesions only. There were no dose-limiting toxicities, dose reductions or discontinuations for treatment-related AEs, and the maximum tolerated dose was not reached. The most common treatment-emergent AEs were fatigue (23%), dehydration (18%) and nausea (18%). All treatment-related AEs were Grade 1 or 2, including nausea (18%) and hot flushes (14%). Fifteen patients had at least 1 scan before the data cutoff date and of these, 3 were not evaluable for ORR due to having bone lesions only. Among the 12 evaluable patients, 4 (33%) achieved partial response: 3 confirmed and one unconfirmed. The clinical benefit rate (CBR) which also includes patients with stable disease ≥24 weeks was 42% (5/12). In the subgroup of evaluable patients harboring a confirmed ESR1 mutation, the ORR was 67% (4/6), the CBR was 83% (5/6) and the median time on treatment was 168 days (range 56-336), with 4 of 7 patients still receiving AC699. Conclusions: Preliminary data from the ongoing phase 1 trial evaluating AC699 indicate promising safety, tolerability, and anti-tumor activity, at doses up to 300 mg orally once daily. A phase 2 study will begin enrolling in early 2024. Clinical trial information: NCT05654532 .

Nationwide real-world practice pattern and clinical data of palbociclib in patients with HR(+), HER2(-) metastatic breast cancer (KCSG BR21-15).

1068 Background: Introduction of cyclin-dependent kinase 4/6 inhibitors in hormone-receptor (HR) positive/ human epidermal growth factor-2 (HER2) negative metastatic breast cancer (MBC) have dramatically improved clinical outcomes in terms of progression-free survival (PFS) and overall survival (OS). Although PALOMA-2 trial has met its primary outcome, it showed relatively shorter OS compared to other pivotal phase III trials with ribociclib and abemaciclib. In Korea, there are limitations to use palbociclib + AI + GnRHa in premenopausal women, and bilateral salpingo-oophorectomy is necessary before starting palbocliclib based on unique approval status. We analyzed the real-world clinical outcome of letrozole + palbociclib, including distinct baseline characteristics in Korea. Methods: Between August 2016 to December 2022, 1,017 HR-positive, HER2 negative postmenopausal MBC patients treated with letrozole with palbociclib as first line treatment were enrolled from 21 tertiary institutions participating Korean Cancer Study Group (KCSG) breast cancer committee. Medical records were collected retrospectively. Primary endpoint was the PFS of letrozole + palbociclib in total patient population and the survival difference according to the method of menopause (natural menopause or bilateral salpingo-oophrectomy, BSO). The key secondary endpoint was OS, post-progression treatment pattern, overall response rate and safety. Results: Median age of the patient was 56 years (range 27~92), with median follow-up duration of 44.8 months (interquantile range 30.8~56.47). Among total patient population, 51 patients (5%) were below 40 years of age. Most patients diagnosed as recurrent breast cancer (633, 62.2%) received adjuvant tamoxifen +/- GnRHa (404, 73.5%). Median PFS and OS was 28.0 months (95% CI 25.53-32.10) and 61.6 months (95% CI 56.93-66.80). Patients who received BSO prior to palbociclib showed similar mPFS compared to natural menopause group (28.07 vs. 28.0 months) (P=0.35). Patients with primary -tamoxifen resistance showed inferior PFS compared to secondary resistance (mPFS 14.63 vs. 27.07 months, P=0.0059). ORR was 47.5% with DCR of 89.6%. Most patients experienced any grade of neutropenia (967 patients, 95.1%), 638 patients with grade 3 neutropenia (62.7%). Among 549 patients with progressive disease, 317 patients (58.1%) received second-line endocrine treatment, with everolimus + exemestane most used. In 204 patients (37.4%) who received cytotoxic chemotherapy, capecitabine was most frequently used (95, 17.3%). About 10% patients participated in clinical trials. Conclusions: To our knowledge, this is the largest country-based real-world data of 1st line palbociclib in Asia. Palbociclib showed OS over 60 months, comparable to other pivotal clinical trials. Further follow-up analysis of PFS2 and subsequent treatment is warranted.

Cognitive function in patients with HR+ advanced breast cancer treated with endocrine therapy with or without CDK4/6 inhibitors in the SONIA trial.

1016 Background: Given the important role of estrogen in normal neuronal function, endocrine treatment for breast cancer may adversely affect cognition, including memory, planning and attention. Previous studies showed mixed results but were often underpowered. It is unknown whether CDK4/6 inhibitors have cognitive side effects. SONIA-EfFECT is a side-study of the SONIA trial that investigates cognitive functioning in HR+ advanced breast cancer patients treated with endocrine therapy with or without CDK4/6 inhibitors. Methods: Patients randomized in the SONIA trial to receive first-line treatment with aromatase inhibitors with (Arm A) or without (Arm B) CDK4/6 inhibition were approached to participate in the SONIA-EfFECT side-study. Patients were asked to identify a female relative or friend without cancer to serve as a cancer-free control. Both patients and controls were asked to complete the Amsterdam Cognition Scan, an online neuropsychological test battery, at baseline and after 9 months. Patients who switched to second-line treatment within nine months were not retested. To prevent confounding effects of imbalance in age, education, and computer use between patient groups and controls, propensity score matching was performed. Baseline cognitive function was assessed by converting raw test scores to standardized Z-scores adjusted for computer use, based on baseline performance in the matched control group. To investigate the effect of endocrine therapy ±CDK4/6 inhibitors over time, standardized regression-based change scores were computed based on baseline and follow-up performance in the matched control group. One-way analyses of variance were conducted to compare baseline performance and cognitive change between the two arms and the matched control group. Results: 260 patients (130 Arm A/130 Arm B) and 196 controls completed baseline assessments. A matched sample of 130 controls was selected. 199 patients (108 Arm A/91 Arm B) and 119 matched controls had complete follow-up assessments. Patients in both study arms performed significantly worse than the controls on the domains of verbal memory, working memory, processing speed, executive function, and motor function. In both patient arms and the controls, standardized regression-based change scores showed limited decline in cognitive function over the 9-month interval. Moreover, minimal differences in cognitive change were observed between the patients treated with and without CDK4/6 inhibitors, and between patients and the controls. Conclusions: HR+ advanced breast cancer patients show worse cognitive function on all cognitive domains compared to a control group without cancer. Nine months of treatment with endocrine therapy with or without CDK4/6 inhibitors does not further worsen cognitive function in this study. Clinical trial information: NCT03425838 .

Evolution of publicly available large language models for complex decision-making in breast cancer care

PurposeThis study investigated the concordance of five different publicly available Large Language Models (LLM) with the recommendations of a multidisciplinary tumor board regarding treatment recommendations for complex breast cancer patient profiles.MethodsFive LLM, including three versions of ChatGPT (version 4 and 3.5, with data access until September 3021 and January 2022), Llama2, and Bard were prompted to produce treatment recommendations for 20 complex breast cancer patient profiles. LLM recommendations were compared to the recommendations of a multidisciplinary tumor board (gold standard), including surgical, endocrine and systemic treatment, radiotherapy, and genetic testing therapy options.ResultsGPT4 demonstrated the highest concordance (70.6%) for invasive breast cancer patient profiles, followed by GPT3.5 September 2021 (58.8%), GPT3.5 January 2022 (41.2%), Llama2 (35.3%) and Bard (23.5%). Including precancerous lesions of ductal carcinoma in situ, the identical ranking was reached with lower overall concordance for each LLM (GPT4 60.0%, GPT3.5 September 2021 50.0%, GPT3.5 January 2022 35.0%, Llama2 30.0%, Bard 20.0%). GPT4 achieved full concordance (100%) for radiotherapy. Lowest alignment was reached in recommending genetic testing, demonstrating a varying concordance (55.0% for GPT3.5 January 2022, Llama2 and Bard up to 85.0% for GPT4).ConclusionThis early feasibility study is the first to compare different LLM in breast cancer care with regard to changes in accuracy over time, i.e., with access to more data or through technological upgrades. Methodological advancement, i.e., the optimization of prompting techniques, and technological development, i.e., enabling data input control and secure data processing, are necessary in the preparation of large-scale and multicenter studies to provide evidence on their safe and reliable clinical application. At present, safe and evidenced use of LLM in clinical breast cancer care is not yet feasible.

Endocrine Disorders in Childhood Brain Tumour Survivors: A Single-Centre Study.

The study aims to determine the prevalence and risk factors for endocrine disorders in childhood brain tumour survivors. Included in the study were 124 childhood brain tumour survivors aged 18 years old or younger with either stable disease or in remission, and had survived for at least 2 years after diagnosis. Demographic data (age at diagnosis, gender, ethnicity, socioeconomic status), clinical clues for endocrine disorders, anthropometrics (weight, height, midparental height), pubertal staging, tumour-related characteristics, treatment modalities and endocrine laboratory measurements at diagnosis and during follow up were obtained. Logistic regression was applied to evaluate risk factors for endocrine disorders in childhood brain tumour survivors. The prevalence of endocrine disorders in childhood brain tumour survivors was 62.1%. The risk factors were high BMI [adjusted odds ratio (OR) 1.29, 95% CI: 1.12 to 1.5], high-risk site [adjusted odds ratio (OR) 7.15, 95% CI: 1.41 to 36.3] and chemotherapy [adjusted odds ratio (OR) 0.18, 95% CI: 0.05 to 0.62]. The prevalence of endocrine disorders in childhood brain tumour survivors in our centre was 62.1%. The significant risk factors were high BMI, tumour location (suprasellar and intrasellar) and chemotherapy.

Long-term Follow-up and Safety of Patients after an Upfront Therapy with Letrozole for Early Breast Cancer in Routine Clinical Care – The PreFace Study

AbstractAdjuvant treatment of patients with early-stage breast cancer (BC) should include an aromatase inhibitor (AI). Especially patients with a high recurrence risk might benefit from an upfront therapy with an AI for a minimum of five years. Nevertheless, not much is known about the patient selection for this population in clinical practice. Therefore, this study analyzed the prognosis and patient characteristics of postmenopausal patients selected for a five-year upfront letrozole therapy.From 2009 to 2011, 3529 patients were enrolled into the adjuvant phase IV PreFace clinical trial (NCT01908556). Postmenopausal hormone receptor-positive BC patients, for whom an upfront five-year therapy with letrozole (2.5 mg/day) was indicated, were eligible. Disease-free survival (DFS), overall survival (OS) and safety in relation to patient and tumor characteristics were assessed.3297 patients started letrozole therapy. The majority of patients (n = 1639, 57%) completed the five-year treatment. 34.5% of patients continued with endocrine therapy after the mandated five-year endocrine treatment. Five-year DFS rates were 89% (95% CI: 88–90%) and five-year OS rates were 95% (95% CI: 94–96%). In subgroup analyses, DFS rates were 83%, 84% and 78% for patients with node-positive disease, G3 tumor grading, and pT3 tumors respectively. The main adverse events (any grade) were pain and hot flushes (66.8% and 18.3% of patients).The risk profile of postmenopausal BC patients selected for a five-year upfront letrozole therapy showed a moderate recurrence and death risk. However, in subgroups with unfavorable risk factors, prognosis warrants an improvement, which might be achieved with novel targeted therapies.

Endocrine therapy in advanced high-grade ovarian cancer: real-life data from a multicenter study and a review of the literature.

In women, ovarian cancer is the eighth most frequent cancer in incidence and mortality. It is often diagnosed at advanced stages; relapses are frequent, with a poor prognosis. When platinum resistant, subsequent lines of chemotherapy are of limited effect and often poorly tolerated, leading to quality of life deterioration. Various studies suggest a hormonal role in ovarian carcinogenesis, with a rationale for endocrine therapy in these cancers. This multicenter, retrospective study assessed the use of endocrine treatment for high-grade ovarian epithelial carcinomas treated between 2010 and 2020. Eighty-one patients with ovarian cancers were included. The median duration of platinum sensitivity was 29 months. We observed a 35% disease control rate with endocrine therapy, and 10% reported symptom improvement. For 19 patients (23.5%), the disease was stabilized for more than 6 months. Median overall survival from diagnosis was 62.6 months. Regarding endocrine therapy predictive factors of response, in a multivariate analysis, 3 factors were statistically significant in favoring progression-free survival: platinum sensitivity (P = .021), an R0 surgical resection (P = .020), and the indication for hormone therapy being maintenance therapy (P = .002). This study shows real-life data on endocrine therapy in ovarian cancer. As it is a low-cost treatment with many advantages such as its oral administration and its safety, it may be an option to consider. A perspective lies in the search for cofactors to aim as future therapeutic targets to improve the effectiveness of hormone treatment by means of combination therapy.

Adverse event signal mining and serious adverse event influencing factor analysis of fulvestrant based on FAERS database

Fulvestrant, as the first selective estrogen receptor degrader, is widely used in the endocrine treatment of breast cancer. However, in the real world, there is a lack of relevant reports on adverse reaction data mining for fulvestrant. To perform data mining on adverse events (AEs) associated with fulvestrant and explore the risk factors contributing to severe AEs, providing a reference for the rational use of fulvestrant in clinical practice. Retrieved adverse event report information associated with fulvestrant from the U.S. Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) database, covering the period from market introduction to September 30, 2023. Suspicious AEs were screened using the reporting odds ratio (ROR) and proportional reporting ratio methods based on disproportionality analysis. Univariate and multivariate logistic regression analyses were conducted on severe AEs to explore the risk factors associated with fulvestrant-induced severe AEs. A total of 6947 reports related to AEs associated with fulvestrant were obtained, including 5924 reports of severe AEs and 1023 reports of non-severe AEs. Using the disproportionality analysis method, a total of 210 valid AEs were identified for fulvestrant, with 45 AEs (21.43%) not listed in the product labeling, involving 11 systems and organs. The AEs associated with fulvestrant were sorted by frequency of occurrence, with neutropenia (325 cases) having the highest number of reports. By signal strength, injection site pruritus showed the strongest signal (ROR = 658.43). The results of the logistic regression analysis showed that concurrent use of medications with extremely high protein binding (≥ 98%) is an independent risk factor for severe AEs associated with fulvestrant. Age served as a protective factor for fulvestrant-related AEs. The co-administration of fulvestrant with CYP3A4 enzyme inhibitors did not show statistically significant correlation with the occurrence of severe AEs. Co-administration of drugs with extremely high protein binding (≥ 98%) may increase the risk of severe adverse reactions of fulvestrant. Meanwhile, age (60–74 years) may reduce the risk of severe AEs of fulvestrant. However, further clinical research is still needed to explore and verify whether there is interaction between fulvestrant and drugs with high protein binding through more clinical studies.

Novel Endocrine Therapeutic Opportunities for Estrogen Receptor-Positive Ovarian Cancer-What Can We Learn from Breast Cancer?

Low-grade serous ovarian cancer (LGSOC) is a rare ovarian malignancy primarily affecting younger women and is characterized by an indolent growth pattern. It exhibits indolent growth and high estrogen/progesterone receptor expression, suggesting potential responsiveness to endocrine therapy. However, treatment efficacy remains limited due to the development of endocrine resistance. The mechanisms of resistance, whether primary or acquired, are still largely unknown and present a significant hurdle in achieving favorable treatment outcomes with endocrine therapy in these patients. In estrogen receptor-positive breast cancer, mechanisms of endocrine resistance have been largely explored and novel treatment strategies to overcome resistance have emerged. Considering the shared estrogen receptor positivity in LGSOC and breast cancer, we wanted to explore whether there are any parallel mechanisms of resistance and whether we can extend endocrine breast cancer treatments to LGSOC. This review aims to highlight the underlying molecular mechanisms possibly driving endocrine resistance in ovarian cancer, while also exploring the available therapeutic opportunities to overcome this resistance. By unraveling the potential pathways involved and examining emerging strategies, this review explores valuable insights for advancing treatment options and improving patient outcomes in LGSOC, which has limited therapeutic options available.

MICAL-L2, as an estrogen-responsive gene, is involved in ER-positive breast cancer cell progression and tamoxifen sensitivity via the AKT/mTOR pathway

Endocrine treatment, particularly tamoxifen, has shown significant improvement in the prognosis of patients with estrogen receptor-positive (ER-positive) breast cancer. However, the clinical utility of this treatment is often hindered by the development of endocrine resistance. Therefore, a comprehensive understanding of the underlying mechanisms driving ER-positive breast cancer carcinogenesis and endocrine resistance is crucial to overcome this clinical challenge. In this study, we investigated the expression of MICAL-L2 in ER-positive breast cancer and its impact on patient prognosis. We observed a significant upregulation of MICAL-L2 expression in ER-positive breast cancer, which correlated with a poorer prognosis in these patients. Furthermore, we found that estrogen-ERβ signaling promoted the expression of MICAL-L2. Functionally, our study demonstrated that MICAL-L2 not only played an oncogenic role in ER-positive breast cancer tumorigenesis but also influenced the sensitivity of ER-positive breast cancer cells to tamoxifen. Mechanistically, as an estrogen-responsive gene, MICAL-L2 facilitated the activation of the AKT/mTOR signaling pathway in ER-positive breast cancer cells. Collectively, our findings suggest that MICAL-L2 could serve as a potential prognostic marker for ER-positive breast cancer and represent a promising molecular target for improving endocrine treatment and developing therapeutic approaches for this subtype of breast cancer.

Current Status and Future Perspectives of Antibody-Drug Conjugates in Hormone Receptor-Positive Breast Cancer.

Breast cancer is the most common cancer type in women. The vast majority of breast cancer patients have hormone receptor-positive (HR+) tumors. In advanced HR+ breast cancer, the combination of endocrine therapy with cyclin-dependent kinase 4/6 (CDK4/6) inhibitors is considered the standard of care in the front-line setting. Nevertheless, resistance to hormonal therapy and CDK4/6 inhibitors eventually occurs, leading to progression of the disease. Antibody-drug conjugates (ADCs) comprise a promising therapeutic choice with significant efficacy in patients with HR+ breast cancer, which is resistant to endocrine treatment. ADCs typically consist of a cytotoxic payload attached by a linker to a monoclonal antibody that targets a specific tumor-associated antigen, offering the advantage of a more selective delivery of chemotherapy to cancer cells. In this review, we focus on the ADC mechanisms of action, their toxicity profile and therapeutic uses as well as on related biomarkers and future perspectives in advanced HR+ breast cancer.

Efficacy analysis of chemotherapy and endocrine therapy combined with targeted drugs after progression on cyclin-dependent kinase 4/6 inhibitor treatment in hormone receptor positive/human epidermal growth factor receptor 2-low metastatic breast cancer

Objective: To evaluate the efficacy of chemotherapy and endocrine therapy combined with targeted drugs after progression on cyclin-dependent kinase 4/6 (CDK4/6) inhibitor treatment in hormone receptor (HR) positive/human epidermal growth factor receptor 2 (HER2)-low metastatic breast cancer. Methods: Patients with metastatic breast cancer diagnosed with HR positive/HER2 low expression at the Fifth Medical Center of PLA General Hospital from October 1, 2018 to September 30, 2023 were retrospectively included. All patients received sequential chemotherapy or sequential endocrine therapy combined with targeted drugs after progression on CDK4/6 inhibitor treatment.The median follow-up was 9 months, and the follow-up ended on October 31, 2023. The patients were divided into chemotherapy group (receiving sequential chemotherapy) and endocrine therapy group (receiving sequential endocrine therapy combined with targeted drugs), according to the treatment plan. Information on demographic data, clinical and pathological diagnosis, treatment regimen, and efficacy evaluation was collected. The basic conditions of patients who may affect the curative effect of different treatment schemes were preset as stratified subgroups, including age, progesterone receptor (PR) status, HER2 status, disease-free survival, number of previous endocrine therapy and chemotherapy, and visceral metastasis. The primary endpoint was progression-free survival (PFS), the secondary endpoints were objective response rate (ORR), clinical benefit rate(CBR) and PFS based on stratification factors. The survival curve was plotted by Kaplan-Meier method, the comparison of PFS between groups was performed by log-rank test, and the comparison of ORR and CBR between groups were performed by χ2 test. Results: A total of 188 patients were included, including 126 patients in the chemotherapy group [all females, aged 29-74 (51±10) years] and 62 patients in the endocrine therapy group [1 male and 61 female, aged 29-77 (51±12) years]. ORR of chemotherapy group was 23.0% (29/126), higher than that of endocrine treatment group [3.2% (2/62)] (P<0.001); The CBR of chemotherapy group and endocrine therapy group were 46.8% (59/126) and 33.9% (21/62), respectively, with no statistical significance (P=0.091). The median PFS of chemotherapy group and endocrine therapy group were 5.0 (95%CI: 4.3-5.7) and 4.0 (95%CI: 1.6-6.4) months, respectively, with no statistical significance (P=0.484). In the preset stratified subgroups, the median PFS of chemotherapy [6.0 (95%CI: 5.4-6.6) months] was longer than that of endocrine combined with targeted therapy [2.0 (95%CI: 1.8-2.2) months] (P<0.001) in PR negative patients; In patients who had progressed on over 2 previous endocrine treatments, the median PFS of chemotherapy [5.0 (95%CI: 3.8-6.2) months] was longer than that of endocrine combined with targeted therapy [2.0 (95%CI: 0.6-3.4) months] (P=0.045). Conclusions: After progression on treatment with CDK4/6 inhibitors for HR-positive/HER2-low expression metastatic breast cancer, both chemotherapy and endocrine therpy combined with targeted drugs are viable treatment options. However, for patients with PR negative or ≥2 lines of endocrine therapy previously, priority should be accorded to chemotherapy.

Does a dedicated endocrine surgery unit impact treatment decision in patients with thyroid disorders? experiences from an endocrine-surgeon naive area in southern india

Does a dedicated endocrine surgery unit impact treatment decision in patients with thyroid disorders? experiences from an endocrine-surgeon naive area in southern india

Abstract PO4-19-08: Randomized phase II study of talazoparib vs talazoparib plus atezolizumab for patients with premenopausal HR+/HER2- metastatic breast cancer harboring homologous recombination deficiency scar (Young-PALETTA, KCSG BR21-09)

Abstract Background Cyclin D kinase-4/6(CDK4/6) inhibitor combined with endocrine treatment have significantly increased progression free survival(PFS) and overall survival(OS) of patients with hormone receptor(HR)-positive/HER2-negative metastatic breast cancer, and currently is a standard 1st line endocrine treatment option. Homologous recombination deficiency(HRD) including germline(g) BRCA1/2 pathogenic mutation is known to be prevalent among young premenopausal patients. Recently several retrospective data suggested that patients with germline BRCA1/2 pathogenic mutation or HRD have poorer outcome with CDK4/6 inhibitor treatment, however there is no prospective evidence. Poly ADP-ribose polymerase(PARP) inhibitors have shown significant benefit over standard chemotherapy in patients with HER2-neg metastatic breast cancer and gBRCA1/2 pathogenic mutation in two Phase 3 trials. Since preclinical data suggested that PARP inhibitors play a role in anti-tumor immune modulation, immunotherapy combined with PARP inhibitors were explored and showed promising antitumor efficacy in several single arm trials. In this trial, we investigate talazoparib and atezolizumab combination compared with talazoparib monotherapy in premenopausal women with HR+/HER2- metastatic breast cancer with HRD-scar after failure with 1st line palbociclib and endocrine treatment combination. Methods This study is a multicenter, randomized, open-label phase II trial comparing talazoparib versus talazoparib with atezolizumab in premenopausal women with HR+/HER2- metastatic breast cancer harboring HRD scar whose disease have progressed with endocrine and palbociclib combination as the 1st-line endocrine treatment. Prior one line of cytotoxic chemotherapy other than platinum for metastatic setting is allowed, but prior palliative endocrine treatment is not allowed. Eligible patients will be pre-screened with tumor tissue biopsy and peripheral blood sampling before endocrine and palbociclib treatment commencement. HRD status is determined through targeted sequencing(SOLIDaccuTestTM by NGeneBio) of tumor tissue and germline HRD genes including BRCA1/2 variant test. Whole genome sequencing and RNA sequencing are performed for biomarker analyses. Patients harboring HRD scar will receive first line endocrine treatment with palbociclib plus aromatase inhibitor with ovarian suppression. After progression with 1L endocrine treatment, patients will be randomized to either talazoparib alone or talazoparib plus atezolizumab combination. Germline BRCA1/2 pathogenic mutation is a stratification factor. Primary endpoint is a progression free survival after randomization(PFS2). Secondary objectives are a composite of PFS1 and PFS2, PFS1, overall survival, patient reported outcome, and biomarkers for treatment response. A total of 178 subjects are required to detect hazard ratio of 0.62 (median PFS2 of at least 10.5 months with talazoparib and atezolizumab combination vs 6.5 months with talazoparib alone), to achieve 80% power at a two-sided a significance level at 10%, considering drop-out rate of 5%. The study period is expected to be 72 months overall(36 months for accrual and randomization and 24 months of follow-up for primary endpoint PFS2). Citation Format: Hee Kyung Ahn, Jieun Lee, Jee Hung Kim, Kyung-Hun Lee, Jee Hyun Kim, Min Hwan Kim, Minsuk Kwon, Han Jo Kim, Kyung Hae Jung, Yeon Hee Park. Randomized phase II study of talazoparib vs talazoparib plus atezolizumab for patients with premenopausal HR+/HER2- metastatic breast cancer harboring homologous recombination deficiency scar (Young-PALETTA, KCSG BR21-09) [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 PO4-19-08.

Abstract PO2-19-07: PROOFS – Pre-/perimenopausal patients with HR+/HER2- EBC with intermediate to high clinical and low genomic risk, treated by endocrine treatment (ET) plus ovarian function suppression (OFS) or chemotherapy followed by ET

Abstract Background During the past years, clinical routine has shifted away from relying solely on clinicopathologic factors toward increasing use of multigene expression assays in guiding treatment decisions regarding adjuvant chemotherapy (CT) for hormone receptor-positive (HR+), HER2-negative (HER2-) early breast cancer (EBC) with 0 to 3 positive lymph nodes. In case of a low genomic risk, there is strong consensus in favor of endocrine treatment (ET) alone for postmenopausal patients, regardless of clinical risk (supported by data from planB, ADAPT, RxPonder, TailorX, MINDACT). However, there is still uncertainty regarding optimal therapy for pre- and perimenopausal patients with a similar clinical/genomic risk profile. Since the observed benefit of CT in this patient group may be partly attributable to CT-induced ovarian function suppression (OFS), some of these patients could be spared CT by adding OFS to endocrine therapy. The West German Study Group (WSG) initiated the PROOFS-registry to create a real-world database on how to optimally treat these patients. Eligibility Criteria PROOFS (NCT05792150) aims at the long-term follow up of pre- or perimenopausal patients with HR+/HER2- EBC with an intermediate to high clinical risk of recurrence and low genomic risk measured by MammaPrint(R). Additional endocrine response assessment (Ki67) after a short preoperative endocrine therapy is encouraged. Up to 25% of the study population may have node-positive disease. Participants undergo standard-of-care treatment at physician´s discretion and according to clinical routine, which may include CT neoadjuvant or adjuvant + ET, ET + OFS in premenopausal, or ET +/- OFS in perimenopausal women. Specific Aims PROOFS aims to give insights in the real-world use of OFS and to confirm an excellent outcome in pre-/perimenopausal women with HR+/HER2- early BC with an intermediate to high clinical risk of recurrence and low genomic risk treated by ET +/- OFS alone (without CT). In addition, quality of life is captured. Statistical Methods The primary objective is to demonstrate the 5-year distant recurrence-free interval (dRFI) in patients treated by ET +/- OFS alone. The null hypothesis H(0) is: 5-year dRFI &amp;lt; 92%. Secondary endpoints for all patients are 5- and 10-year dRFI, distant disease-free survival (dDFS), overall survival (OS), breast cancer-free interval (BCFI), quality of life (QLQ BR23 and QLQ-C30) and therapy adherence. Cox regression models, Kaplan-Meier method and log-rank tests will be applied for survival analysis. Linear mixed models will be utilized to quantitatively describe the course of quality of life-scores as well as therapy adherence, and to conduct group comparisons. Present and Target Accrual The study is open for recruitment of 1500 patients (approximately 20% receiving CT and 80% receiving ET +/- OFS) at up to 100 centers in Germany (June 2023: 24 open for recruitment). Funding AGENDIA N.V., Amsterdam Contact Information rachel.wuerstlein@med.uni-muenchen.de Citation Format: Rachel Wuerstlein, Lotta Ada Fischer, Nadia Harbeck, Monika Graeser, Ulrike Nitz, Matthias Christgen, Sherko Kuemmel, Christine zu Eulenburg, Matthias Warm, Oleg Gluz. PROOFS – Pre-/perimenopausal patients with HR+/HER2- EBC with intermediate to high clinical and low genomic risk, treated by endocrine treatment (ET) plus ovarian function suppression (OFS) or chemotherapy followed by ET [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 PO2-19-07.