ER-positive HER2-negative Breast Cancer Research Articles

Abstract PO5-01-14: Genomic risk analyses in patients with clinical low risk ER-positive HER2-negative early breast cancer developing an early metastatic event

Abstract Background: Over the past decade, there have been notable changes in the definition of risk estimation in patients with early-stage breast cancer (EBC). Specifically, within the timeframe of 2000 to 2017, following Estrogen Receptor (ER) positive and HER2-negative EBC cases were classified as low risk according to the University Hospitals of Leuven (UHL) criteria of that time: if ER H-score was >200: all patients with tumors N0 and Grade (G) 1, ≤pT2; or G2-3 pT1a-b; in patients ≥40 years with tumors N0 and G2 pT1c-2 or G3 pT1c; in patients ≥ 55 years with tumors N0 G3 pT2 or N1 any Grade, pT≤2. For lower H-scores, other criteria applied. However, despite undergoing endocrine therapy, a subset of these patients with clinically low-risk tumors unexpectedly experienced metastasis within five years of initial diagnosis. This unforeseen outcome may indicate potential undertreatment, as these patients did not receive adjuvant chemotherapy. We have conducted a case-cohort study of those patients with early relapse and performed the current clinical risk assessment methods and genomic risk analyses. Methods: In this study, we included patients with ER-pos, HER2-neg early-stage breast cancer diagnosed between 1-1-2000 and 31-12-2017, who were classified as low-risk tumors by UHL guidelines at that time, who were older than 35 but younger than 71 years, had an unilateral, unifocal breast tumor with tumor size up to 5 cm. These patients did not receive adjuvant chemotherapy. We selected the patients that experienced early distant recurrence, defined as distant recurrence (DR) within 5 years after the initial diagnosis. To ensure comparability for the analyses they were matched to controls for grade, menopausal status, tumor size, lymphovascular invasion, progesterone receptor status, and the year of diagnosis. For each patient, we have calculated the clinical risk score according to the criteria outlined by Mymammaprint.com, based on the modified Adjuvant Online tool used in the MINDACT trial. For the analysis, formalin-fixed paraffin-embedded (FFPE) breast tumor tissue samples were subjected to in-house validated targeted RNA-based Mammaprint(MP) analysis by NGS (MP Agendia). Results: Of the 3190 patients with EBC at UHL during the study period, 2476 patients were considered for this analysis and fitted the clinical low-risk criteria defined low-risk at UHL. Among those, only 42 or 1.7% of the eligible cohort had developed metastasis within 5 years. Tissue for MP analysis was available for 35 of these cases and for their matched control. Due to technical failure, the 1:1 matching was lost and MP results were known for 28 cases and 27 controls. The patient and tumor characteristics of both groups were comparable. In this UHL clinical low-risk group, 21/28 (75%) cases would be identified as clinical high-risk by MyMammaprint.com and 18/27 (67%) controls. We identified 13 patients (46.43%) with high genomic risk within the group with DR and 9 (33.33%) within the control group. There was no statistically significant difference (p=0.412) in the proportion of genomically high-risk patients within the group with DR compared to the control group. Conclusions: In a database of patients with EBC of whom 98% did not develop metastasis within 5 years, we observed in a small series of chemotherapy naïve patients with early DR and UHL-defined clinical low-risk tumors, that nearly half had a genomically high risk of distant metastasis. Albeit numerically higher than the matched-control group, this observation was not significant and would warrant a larger sample size and power to confirm these results. Table. Genomic versus Clinical Risk by MyMammaprint.com Citation Format: Josephine Van Cauwenberge, Hava Izci, Hans Wildiers, Sileny Han, Christine Desmedt, Giuseppe Floris, Sara Vander Borght, Ann Smeets, Ines Nevelsteen, Isabelle Vanden Bempt, Patrick Neven. Genomic risk analyses in patients with clinical low risk ER-positive HER2-negative early breast cancer developing an early metastatic event [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 PO5-01-14.

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

Abstract Background: In estrogen receptor (ER)-positive human epidermal growth factor receptor2 (HER2)-negative early breast cancer (EBC) patients, NCCN treatment guideline recommend 21-gene tests for decision of adjuvant chemotherapy if tumor size is over 0.5cm or node positive disease. In addition, GenesWellTM BCT is a prognostic assay that predict the risk of recurrence in patients with ER-positive HER2-negative and nodal stage 0-1 EBC. According to gene tests, EBC patients with high recurrence risk would have help from adjuvant chemotherapy to increase the rate of disease free survival but toxicities of chemotherapy are not negligible. Therefore, the effort for escaping adjuvant chemotherapy has been performed and currently CDK4/6 inhibitor would be considered as the substitute for cytotoxic chemotherapy in ER-positive HER2-negative EBC patients. Methods: HIPEx trial is a multi-center, phase II clinical trial to determine the efficacy of adjuvant palbociclib plus endocrine therapy in ER-positive HER2-negative EBC with high recurrence score according to GenesWellTM BCT (NCT04247633). Eligible patients are women who received curative surgery and diagnosed as ER-positive, HER2-negative and pathologic stage T1b-T2 and/or N0-1. Clinical recurrence risk is high according to the modified Adjuvant! Online guideline and GenesWellTM BCT score is 4 or more which being genomic high risk. Other criteria include ECOG performance status ≤1, adequate organ functions and availability of an archival surgical specimens. Patients receive palbociclib 125mg once daily for 21 days of 28-day cycle plus tamoxifen or aromatase inhibitor (anastrozole, letrozole or exemestane) once daily for every day. Palbociclib would be taken for two years and endocrine therapy for five years or more. If adjuvant radiotherapy is required, palbociclib should be taken two weeks after the end date of radiotherapy. If patients are premenopausal status, GnRH agonist is allowed. Primary endpoint is 3-year event free survival (EFS) rate of high clinical and genetic risk ER-positive EBC. Secondary endpoints include 3-year overall survival, quality of life, safety and tolerability of palbociclib with endocrine therapy as an adjuvant setting, exploratory analysis of predictive and prognostic biomarkers and the performance of GenesWellTM BCT for 3-year EFS rate. In total, 578 patients would be enrolled in this trial. Based on the previous results of GenesWell™ BCT in Korea, the 3-year EFS rate for the past control group (chemotherapy followed by endocrine therapy) is 87.0% and the treatment group in this clinical trial is assumed to be 90.5%.(hazard ratio for EFS = 0.717). Null hypothesis is the 3year-EFS rate in patients received adjuvant palbociclib and endocrine therapy is not less than that of the past control group. Alternative hypothesis is the 3year-EFS rate of this trial is less than that of the past control group (one-sided). Significance level is 0.025, power is 0.80. Considering 10% drop out rate, 4-years of accrual patient enrollment and 3-years of follow up period, 578 patients were required in this clinical trial. Citation Format: Ji-Yeon Kim, Sung Hoon Sim, Jieun Lee, In Hae Park, Kyong Hwa Park, Seock-Ah Im, Jee Hung Kim, Kyoung Eun Lee, Jeong Eon Lee, Jai Min Ryu, Young Kee Shin, Yeon Hee Park. HIPEx: Adjuvant palbociclib plus endocrine therapy in ER-positive HER2-negative early breast cancer with high recurrence score according to GenesWellTM BCT; a multi-center single arm phase II clinical trial (KCSG BR 19-13) [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-20-03.

Abstract PO4-07-05: Clinical evaluation of image-based risk profiling in breast cancer histopathology and comparison to an established gene expression assay

Abstract Background: Among oestrogen receptor (ER)-positive and human epidermal growth factor receptor 2 (HER2)-negative early breast cancer, a significant proportion of patients are categorised as intermediate risk, based on classic clinico-pathological variables, thus providing limited information to guide adjuvant chemotherapy decisions. Prognostic risk profiling is an integrated part of modern breast cancer diagnostics to provide additional risk information for this patient group. Among the established prognostic assays based on gene expression, the Prosigna assay is widely used and provides an individual risk of recurrence (ROR) score and identifies intrinsic subtypes with associated survival outcomes. Pioneering artificial intelligence-based precision diagnostics, Stratipath Breast, is a deep learning-based image analysis tool that utilises digitised histopathological whole slide images to stratify intermediate risk patients in terms of risk of recurrence. Materials and methods: The study included 234 invasive breast tumours from patients with early ER-positive HER2-negative breast cancer, clinically assessed as intermediate risk tumours and eligible for chemotherapy. All tumours had therefore previously been analysed by the Prosigna assay in clinical routine at point of diagnosis between 2020 and 2022 at the Karolinska University Hospital and Södersjukhuset, Stockholm, Sweden. Clinicopathological data including Prosigna results (ROR score, risk group and intrinsic subtype) were extracted from medical records, along with the corresponding archived haematoxylin and eosin (HE)-stained formalin-fixed paraffin-embedded tissue slides. The HE slides were subsequently digitised and analysed by the Stratipath Breast tool. The agreement between the two tests for risk stratification was evaluated in this real-world breast cancer case series. Results: The Prosigna assay classified 76 (32.5%), 110 (47.0%) and 48 (20.5%) tumours as low, intermediate and high risk, respectively. The Stratipath Breast analysis identified 116 (49.6%) tumours as low risk and 118 (50.4%) as high risk. Among Prosigna intermediate risk tumours, 52 (47.3%) were stratified as low risk and 58 (52.7%) as high risk by Stratipath Breast. The overall agreement between the two tests for low risk and high risk groups was 71.0%, with a Cohen’s linear kappa of 0.42. Twelve of the 48 Prosigna high risk cases were classified as Stratipath low risk. ROR scores were higher in the Stratipath high risk group compared to the low risk group (p < 0.001), across all cases as well as in the Prosigna intermediate group. Among the 176 histological grade (NHG) 2 tumours, 97 (55.1%) and 79 (44.9%) were stratified as Stratipath low risk and high risk, respectively, whereas 66 (37.5%), 83 (47.2%) and 27 (15.3%) were stratified as Prosigna low, intermediate and high risk, respectively. The majority of NHG1 (10 of 12) and NHG3 (37 of 46) tumours were stratified as Stratipath low risk and high risk, respectively. For both risk profiling tests, NHG and Ki67 proliferation index differed between risk groups. Conclusions: In this study of clinically assessed intermediate risk ER-positive HER2-negative breast cancer, we observed a moderate agreement between Prosigna and Stratipath Breast for low risk and high risk groups. In addition, image-based risk profiling stratified more of the NHG2 tumours as high risk. Citation Format: Stephanie Robertson, Yinxi Wang, Wenwen Sun, Emelie Karlsson, Sandy Kang Lövgren, Mattias Rantalainen, Johan Hartman. Clinical evaluation of image-based risk profiling in breast cancer histopathology and comparison to an established gene expression assay [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 PO4-07-05.

Abstract PO3-05-05: The effect of histological breast cancer subtype on progression free survival in patients with CDK4/6 inhibitors

Abstract Background: Multiple trials have proven that adding CDK4/6 inhibitors to endocrine treatment increases progression free (PFS) and overall survival (OS) of patients with metastatic estrogen receptor (ER)-positive HER2 negative breast cancer. However, only limited evidence is available of treatment efficacy of CDK4/6 inhibitors for invasive lobular carcinoma (ILC). This retrospective study aims to compare treatment duration of the three FDA/EMA approved CDK4/6 inhibitors in patients with no special type (NST) breast cancer versus patients with ILC. Methods: All patients with metastatic ER-positive HER2-negative breast cancer who were treated with a CDK4/6 inhibitor (1st, 2nd; 3rd line) in University Hospitals Leuven between December 2014 and February 2023, were included. A comparison of PFS and OS was made between patients with NST and ILC by use of the Kaplan Meier method. Other histological subtypes as well as mixed subtypes were excluded. Uni- and multivariable cox regression models were performed to quantify the association of histological subtype with PFS and OS. Results: A total of 418 patients were included of which 119 (28.5%) patients with ILC (median age at primary diagnosis 59 years, range 36 – 89 years) and 299 (71.5%) patients with NST (median age at primary diagnosis 55 years, range 23 – 90 years). Median follow-up was 26.8 months (range 1.1 – 88.1 months). Median PFS was 15.2 months (range 1.0 – 74.6 months) and 14.7 months (range 1.0 – 89.3 months) for patients with ILC and NST respectively. The OS rate after 60 months follow up was 39.2 % (CI 26.8 – 51.4) for ILC and 40.1% (CI 32.2 – 47.8) for NST. As shown in table 1, clear differences were observed in PFS rates after 12, 24 and 60 months between patients with NST that received CDK4/6 inhibitors in first line versus second or third line. These differences were less apparent for patients with ILC. For both NST and ILC, endocrine resistance at start of CDK4/6 inhibition impacted PFS rates negatively (table 2). In multivariable analyses, histological subtype was not predictive for CDK4/6 inhibition outcome (PFS: hazard ratio (HR) 0.996, CI 0.728 – 1.364, p-value 0.981; OS: HR 0.872, CI 0.602 – 1.263, p-value 0.468). Endocrine sensitivity vs. resistance at the time CDK4/6 inhibitor was started, was proven to be predictive for both PFS (HR 0.478, CI 0.337 – 0.678, p-value < 0.001) and OS (HR 0.528, CI 0.347 – 0.804, p-value 0.003). Conclusion: In our center, the histological subtype of breast cancer did not seem to impact PFS and OS significantly after treatment with CDK4/6 inhibition. Patients with NST seemed to have an increased benefit in PFS from treatment with CDK4/6 inhibition in first line as compared to later lines. While for patients with ILC, no difference between treatment lines were observed. Therefore, clinicians might be able to safely postpone CDK4/6 inhibitors to second- or third-line treatment in patients with metastatic ILC. Table 1: PFS rates by histological subtype and line of CDK4/6 treatment Table 2: PFS rates by histological subtype and endocrine sensitivity at start of CDK4/6 inhibition Citation Format: Cedric Bauters, Karen Van Baelen, Hans Wildiers, Giuseppe Floris, Sileny Han, Patrick Berteloot, Thaïs Baert, Ann Smeets, Ines Nevelsteen, Yannick Van Herck, Anne Deblander, Chantal Remmerie, Lieke Dullens, Maxime Van Houdt, Annouschka Laenen, Christine Desmedt, Patrick Neven. The effect of histological breast cancer subtype on progression free survival in patients with CDK4/6 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 PO3-05-05.

316P Comprehensive characterization of the HER2-enriched intrinsic molecular subtype in ER-positive HER2-negative breast cancer

316P Comprehensive characterization of the HER2-enriched intrinsic molecular subtype in ER-positive HER2-negative breast cancer

473P Predictive factors for drug-induced liver injury in patients with ER-positive HER2-negative metastatic breast cancer treated with first-line cyclin-dependent kinase 4/6 inhibitors

473P Predictive factors for drug-induced liver injury in patients with ER-positive HER2-negative metastatic breast cancer treated with first-line cyclin-dependent kinase 4/6 inhibitors

Multigene profiles to guide the use of neoadjuvant chemotherapy for breast cancer: a Copenhagen Breast Cancer Genomics Study

Estrogen receptor (ER) and human epidermal growth factor 2 (HER2) expression guide the use of neoadjuvant chemotherapy (NACT) in patients with early breast cancer. We evaluate the independent predictive value of adding a multigene profile (CIT256 and PAM50) to immunohistochemical (IHC) profile regarding pathological complete response (pCR) and conversion of positive to negative axillary lymph node status. The cohort includes 458 patients who had genomic profiling performed as standard of care. Using logistic regression, higher pCR and node conversion rates among patients with Non-luminal subtypes are shown, and importantly the predictive value is independent of IHC profile. In patients with ER-positive and HER2-negative breast cancer an odds ratio of 9.78 (95% CI 2.60;36.8), P < 0.001 is found for pCR among CIT256 Non-luminal vs. Luminal subtypes. The results suggest a role for integrated use of up-front multigene subtyping for selection of a neoadjuvant approach in ER-positive HER2-negative breast cancer.

250P Liver Toxicity (LT) in patients (pts) with ER-positive HER2-negative metastatic breast cancer (MBC) treated with first-line Cyclin-Dependent Kinase 4/6 inhibitors (CDKi)

A meta-analysis of all Ph3 trials with CDKi plus endocrine therapy (ET) has established 13% incidence of LT of any grade (vs 5.4% with ET alone). However, the clinical characteristics of these pts and the predictive factors associated with developing LT remain unknown. All MBC pts treated with first-line CDKi in Vall d’Hebron Hospital from 2018 to 2022 were analyzed retrospectively. LT was defined as ≥G2 AST/ALT elevation. Clinical and laboratory characteristics, oncologic disease status, and evolution of liver function tests for those pts were registered. Among 472 pts treated, 26 (5.5%) developed LT, G2 in 11 (42%), G3 in 13 (50%) and G4 in 2(8%) without LT related-deaths. LT occurred in 3%, 8% and 11.6% of pts receiving palbociclib, abemaciclib and ribociclib, respectively. Baseline characteristics: median (M) age 61y, premenopausal 54%, overweight/obese 59%, 11.5% alcohol consumers, 27% current/former smokers, 27% stage IV de novo and 27% with liver metastases. As for cardiovascular risk factors: 32% had dyslipemia, 31% liver steatosis at CT scan and 26.9% arterial hypertension. Concomitant ET was letrozole 54%, fulvestrant 35% and anastrozole 11%. LT occurred after 7 cycles (M), and 218 days (IQR 37-399). Only 1 pt receiving abemaciclib had G4 bilirubin elevation without fulfilling Hy's Law criteria. In 88.5% LT returned to basal in 44 days (M) (IQR 26-61). CKDi was reintroduced in 58% of pts; 8% at the same dose, 54% at -1 dose level, and 38% at -2 dose level. Of them, 61.5% had a 2nd LT episode which resolved in 62.5% in 26 days (M) (IQR 14-49). The results by type of CDKi are shown in the table. Table: 250PCharacteristicsPalbociclibAbemaciclibRibociclibLT pts/Total pts8/2839/1129/77M days until LT1166398LT resolved87%75%100%M days to resolution282646Relapse of LT20%75%66%M days until relapse142011 Open table in a new tab In our cohort of pts 5.5% developed LT. LT reached G3 in 58% of cases, mainly with ribociclib. A high proportion of those pts had ≥25 BMI and 31% had liver steatosis. LT was mainly reversible with no fatal cases. These results could help to develop prediction scores to identify patients at risk of developing severe LT.

Abstract 4477: DIACC3010, optimized inhibitor of S6 kinase, combined with endocrine therapy, has potent antitumor activity in treatment-resistant ER-positive HER2-negative metastatic breast cancer

Abstract Background: Ribosomal protein S6 kinase (S6K) is a key regulator of estrogen receptor (ER) function, and its high expression is associated with poor clinical outcomes in breast cancer (BC). Recent data have demonstrated that S6K is involved in resistance to CDK4/6 inhibitors in metastatic BC (MBC). DIACC3010 (formerly M2698) is an oral brain-penetrant potent inhibitor of S6K. By design, DIACC3010 also selectively inhibits AKT1 and AKT3, while sparing AKT2. DIACC3010 was previously evaluated in a phase 1 trial (NCT01971515). We performed exploratory correlative analyses of the phase 1 trial in ER+ HER2-negative MBC patients in addition to nonclinical experiments to evaluate its role in the CDK4/6 and endocrine therapy (ET) resistant setting. Methods: DIACC3010 was evaluated as monotherapy, or combined with either trastuzumab or tamoxifen, in a multicenter phase 1 trial that accrued 101 patients with advanced/refractory solid tumors (Tsimberidou et al, J Hematol Oncol 2021 14(1):127). The current analysis focused on patients with ER+ HER2-negative MBC and aimed to explore the efficacy of DIACC3010 according to ESR1 mutational status. DIACC3010 was also evaluated in tamoxifen resistant patient-derived xenograft (PDX) mouse models, both alone and combined with tamoxifen. Results: Twenty patients were evaluable at baseline for their tumor mutational status and included in the analysis. Median age was 60 years and median number of prior lines of therapy was 5.5. Twelve of 20 (60%) patients had received prior treatment with CDK4/6 inhibitors. Nine of 20 patients (45%) had ESR1 mutations, of whom 4 had received CDK4/6 inhibitor. Median progression free survival was 5.6 months in patients with ESR1 mutations, and 2.6 months in patients with ESR1 wild-type tumors. Among the 13 ER+ BC PDX models evaluated, 10 provided interpretable results and 4 were found resistant to tamoxifen. The combination of DIACC3010 and tamoxifen significantly reduced tumor growth in 6/10 (60%) of all PDX models, and in 4/4 (100%) of the tamoxifen-resistant PDX models. Conclusions: Exploratory analyses from the phase 1 trial, along with nonclinical efficacy in PDX models, demonstrate that DIACC3010 may have antitumor activity in MBC patients with ET resistance. Experiments are underway to assess nonclinical efficacy of DIACC3010 combination with elacestrant or CDK4/6 inhibitors in various models of ER+ MBC, including ET resistant. Citation Format: Christel Navarro, Apostolia Maria Tsimberidou, Cecile Bougeret, Elsa Borghi, Dominique Bridon, Helene Sicard. DIACC3010, optimized inhibitor of S6 kinase, combined with endocrine therapy, has potent antitumor activity in treatment-resistant ER-positive HER2-negative metastatic breast cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4477.

Long-term Survival in Breast Cancer Patients Is Associated with Contralateral Parenchymal Enhancement at MRI: Outcomes of the SELECT Study.

Background Several single-center studies found that high contralateral parenchymal enhancement (CPE) at breast MRI was associated with improved long-term survival in patients with estrogen receptor (ER)-positive and human epidermal growth factor receptor 2 (HER2)-negative breast cancer. Due to varying sample sizes, population characteristics, and follow-up times, consensus of the association is currently lacking. Purpose To confirm whether CPE is associated with long-term survival in a large multicenter retrospective cohort, and to investigate if CPE is associated with endocrine therapy effectiveness. Materials and Methods This multicenter observational cohort included women with unilateral ER-positive HER2-negative breast cancer (tumor size ≤50 mm and ≤three positive lymph nodes) who underwent MRI from January 2005 to December 2010. Overall survival (OS), recurrence-free survival (RFS), and distant RFS (DRFS) were assessed. Kaplan-Meier analysis was performed to investigate differences in absolute risk after 10 years, stratified according to CPE tertile. Multivariable Cox proportional hazards regression analysis was performed to investigate whether CPE was associated with prognosis and endocrine therapy effectiveness. Results Overall, 1432 women (median age, 54 years [IQR, 47-63 years]) were included from 10 centers. Differences in absolute OS after 10 years were stratified according to CPE tertile as follows: 88.5% (95% CI: 88.1, 89.1) in tertile 1, 85.8% (95% CI: 85.2, 86.3) in tertile 2, and 85.9% (95% CI: 85.4, 86.4) in tertile 3. CPE was independently associated with OS, with a hazard ratio (HR) of 1.17 (95% CI: 1.0, 1.36; P = .047), but was not associated with RFS (HR, 1.11; P = .16) or DRFS (HR, 1.11; P = .19). The effect of endocrine therapy on survival could not be accurately assessed; therefore, the association between endocrine therapy efficacy and CPE could not reliably be estimated. Conclusion High contralateral parenchymal enhancement was associated with a marginally decreased overall survival in patients with estrogen receptor-positive and human epidermal growth factor receptor 2-negative breast cancer, but was not associated with recurrence-free survival (RFS) or distant RFS. Published under a CC BY 4.0 license. Supplemental material is available for this article. See also the editorial by Honda and Iima in this issue.

Abstract P5-02-49: Efficacy of subsequent-abemaciclib treatment after disease progression on palbociclib combined with endocrine therapy in patients with ER-positive HER2-negative metastatic breast cancer

Abstract Purpose: Currently, CDK4/6i combined with endocrine therapy (ET) has become the standard of care as first- or second-line treatment for estrogen receptor-positive (ER+) human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (MBC). However, at present, there are no guidelines for the selection of appropriate treatments after disease progression on prior CDK4/6i treatment combined with ET. Therefore, this retrospective study aimed to verify the efficacy and evaluate predictive factors of clinical outcomes in the patients with ER+/HER2- MBC during subsequent-abemaciclib treatment after disease progression on prior-palbociclib combined with ET. Methods: In total, 81 patients with ER+/HER2- MBC were treated with palbociclib and ET at our medical center between December 2017 and November 2020. Among them, 25 patients who received subsequent-abemaciclib after disease progression on prior-palbociclib were included. All patients provided informed consent for the indicated treatment. Clinicopathological variables were compared using Fisher’s exact test. The Mann–Whitney U test was used to compare categorical variables. PFS and time to chemotherapy (TTC) were estimated using Kaplan–Meier analysis with 95%CIs. Results: The median age was 69 years, and four women were premenopausal. Stage IV disease occurred in 28.0% (7/25) and visceral metastases were observed in 68.0% (17/25) of the patients. The treatment line of prior-palbociclib was the first-line in 3 (12.0%), second-line in 11 (44.0%), and third- and late-line in 11 patients (44.0%). The median PFS of prior-palbociclib plus ET was 6.3 months (95%CI=5.814–6.786). Subsequent-abemaciclib combined with fulvestrant after disease progression on prior-palbociclib was administered in 64.0% (16/25) of the patients. Median numbers of previous ET and chemotherapy of subsequent-abemaciclib were 2 and 0, respectively. Subsequent-abemaciclib after disease progression on prior-palbociclib resulted in an ORR and clinical benefit rate (CBR) of 16.0% (4/25) and 44.0% (11/25), respectively (Table 1). Kaplan–Meier curve analysis showed that the median PFS was 5.3 months (95%CI=3.082–7.518). Univariate analysis revealed that the best overall response (BOR) ≥PR and progression-free interval (PFI) ≥6 months in prior-palbociclib contributed to better clinical outcomes. Moreover, in multivariate analysis, BOR to prior-palbociclib was the only independent predictive factor for PFS (HR=0.190; 95%CI=0.050–0.722; p=0.015) (Table 2). With regard to grade ≥3 TRAEs in the subsequent-abemaciclib, neutropenia and diarrhea were observed in 16.0% (4/25); appetite loss and fatigue in 12.0% (3/25); leukopenia and anemia in 8.0% (2/25); and thrombocytopenia and liver dysfunction in 4.0% (1/25) of patients. Twelve patients (48.0%) required dose reduction due to TRAEs grade ≥3 in subsequent-abemaciclib. Of them, 10 patients required one dose-level reduction and 2 needed two dose-level reductions. Three patients (12.0%) required dose discontinuation: two had uncontrollable appetite loss and nausea and one had pneumonia. Of the 25 patients, 12 were not administered any prior chemotherapy and the median TTC in those treated with subsequent-abemaciclib was 33.9 months (95%CI=11.334–56.136). Next-line treatment after disease progression on subsequent-abemaciclib in the patients who were not administered prior chemotherapy was performed in 2 (8.0%) who were treated with ET and in 12 (48.0%) who were treated with chemotherapy (1 taxane-based, 7 eribulin, and 4 oral 5-fluorouracil). The median PFS in patients treated with chemotherapy after disease progression on subsequent-abemaciclib treatment was 6.2 months (95%CI=3.484–8.916). Table 1. Best overall response rate in patients with ER+/HER- MBC who were treated with subsequent-abemaciclib after disease progression on prior-palbociclib Table 2. Univariate and multivariate analyses of the progression-free survival in patients with ER+/HER2- MBC treated with subsequent-abemaciclib after progression on prior-palbociclib Citation Format: Hirohito Seki, Taketo Nakai, Ken Shimizu. Efficacy of subsequent-abemaciclib treatment after disease progression on palbociclib combined with endocrine therapy in patients with ER-positive HER2-negative metastatic breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P5-02-49.

Abstract P3-01-13: Palbociclib, ribociclib and abemaciclib in real-world data: risk of disease progression on first-line treatment of metastatic breast cancer

Abstract Introduction and objectives: Cyclin dependent kinase (CDK) 4/6 inhibitors along with endocrine therapy (ET) is the standard first-line for endocrine receptor (ER)-positive HER2-negative metastatic breast cancer. Three CDK 4/6 inhibitors have the FDA and EMA approval: abemaciclib, palbociclib and ribociclib. They appear to have notable differences in their pharmacokinetic characteristics and ability to inhibit every cyclin. Nevertheless, the natural history of disease associated with each CDK 4/6 inhibitor remains unclear. The aim of this study is to establish a risk prediction model for disease progression under the different therapeutic regimes and assess whether there are differences in terms of efficacy between them. Methods: This is a retrospective observational study in which patients treated with ET plus abemaciclib, palbociclib or ribociclib as front line for metastatic breast cancer in Virgen del Rocio Hospital between April 2014 and April 2021 were selected. Patients in this population were followed for a period of 36 months. They were studied according to their clinical characteristics and disease outcome using descriptive analysis. The risk of progression was studied by a transversal method using a univariate logistic regression model. Moreover, Kaplan Meier curves were used to estimate progression-free survival (PFS) and the Breslow test to estimate the p value. All statistical analyses were performed with SPSS 28.0 (Statistical Package for the Social Sciences). Results: A total of 189 patients were selected. 55(29.1%) of them received abemaciclib, 83(44%) palbociclib and 51(27%) ribociclib. 50(27%) patients had de novo metastatic disease, while 139(73%) were recurrences of previous disease. Almost half of the patients (45%) received fulvestrant and 104 (55%) patients received aromatase inhibitors. Table 1 represents the proportion of patients with visceral involvement and endocrine resistance in each arm. The univariate logistic regression model showed that patients treated with palbociclib had 2.36(CI95% 1.165-4.765) times the risk of progression compared to abemaciclib, while patients treated with ribociclib had 2.50(CI95% 1.139-5. 475) times the risk of progression compared to abemaciclib. Overall PFS was 30.03 months. A tendency towards best PFS with abemaciclib in comparison with the other CDK 4/6 inhibitors was appreciated, but it did not reach statistical significance (abemaciclib-palbociclib p=0.289; abemaciclib-ribociclib; p= 0.293; palbociclib-ribociclib p=0.979). Conclusions: In our sample of patients with ER-positive HER2-negative metastatic breast cancer treated with the different CDK 4/6 inhibitors as front line therapy, patients with abemaciclib achieved a lower risk of progression and a trend toward longer PFS. Further follow-up will be necessary to determine whether abemaciclib provides greater benefit in PFS. Table 1. Proportion of patients with visceral involvement and endocrine resistance in each arm. Visceral metastases: Liver, Lung, central nervous System; Non-Visceral: Bone, skin, Lymph node. Citation Format: Mónica Cejuela, M. ángeles Castilla, Marta Benavent, Sonia Molina-Pinelo, Maria A Dominguez-Cejudo, Ana Gil, Alejandro Falcon, Francisco Javier Salvador Bofill. Palbociclib, ribociclib and abemaciclib in real-world data: risk of disease progression on first-line treatment of metastatic breast cancer. [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P3-01-13.

Abstract GS3-02: GS3-02 Camizestrant, a next generation oral SERD vs fulvestrant in post-menopausal women with advanced ER-positive HER2-negative breast cancer: Results of the randomized, multi-dose Phase 2 SERENA-2 trial

Abstract Background Camizestrant (C), a next-generation oral selective estrogen receptor (ER) antagonist and degrader (ngSERD) has shown promising clinical activity in ER+ breast cancer (BC) in the Phase 1 SERENA-1 study1,2 with a dose-dependent safety profile. The Phase 2 randomized SERENA-2 study (NCT04214288) initially assessed three doses of C vs fulvestrant (F) in post-menopausal women with ER+ HER2˗ BC with disease recurrence or progression after ≤1 endocrine therapy (ET) in the advanced setting. Methods SERENA-2 evaluated efficacy and safety of C 75, 150 or 300 mg monotherapy QD vs F (per label). Eligible patients were randomized 1:1:1:1. The Primary objective was to determine clinical efficacy of C vs F by investigator-assessed progression-free survival (PFS). Secondary endpoints included objective response rate, response duration, clinical benefit rate at 24 weeks, overall survival and safety. Patients had no prior F or oral SERD and ≤1 ET and ≤1 chemotherapy (CTX) in the advanced setting. To assess the impact of prior CDK4/6 inhibitor (CDK4/6i) treatment, randomization was stratified so that 50% of patients had prior CDK4/6i. Planned enrolment of 288 patients began in April 2020. The C 300 arm was closed after 20 patients were enrolled, changing target enrolment to 236. By August 2021, 240 patients had been randomized. Primary analysis was triggered when 108 progression events (75% maturity) had occurred in the best performing pair (C vs F) in August 2022. Efficacy analyses compared C 75 and 150 mg doses with F, with no formal analyses of C 300 vs F. 108 events for pairwise comparison vs F gave 86% power at the 2-sided 10% significance level. Primary analyses used a Cox proportional hazards model to compare PFS, adjusting for prior CDK4/6i and lung/liver metastases. ESR1 mutations (ESR1m) were detected in plasma samples using next-generation sequencing. Results 119/240 (49.6%) patients had had prior CDK4/6i therapy. At baseline, 88 (36.7%) patients had detectable ESR1m and 140 (58.3%) had lung/liver metastases. Prior CTX or ET rates in the advanced setting were 19.2 and 65.4%. Treatment-emergent adverse events (AEs) (grade ≥3) occurred in 77.0 (12.2), 90.4 (21.9) and 68.5 (13.7) % of patients in the C 75, C 150 and F arms. AEs leading to treatment discontinuation occurred in 2.7, 0 and 0% of patients in the C 75, C 150 and F arms. The most common AEs considered by the investigator to be causally related to study drug were photopsia (18.4%) and (sinus) bradycardia (13.6%) – all were grade 1 or 2. Hot flush (2.7%) and myalgia (2.7%) were the most common AEs related to F. Conclusions SERENA-2 is the first Phase 2 trial investigating multiple dose levels of an ngSERD vs F in post-menopausal women with advanced ER+ HER2˗ BC with disease recurrence or progression after ≤1 ET in the advanced setting. C at both 75 and 150 mg dose levels showed a statistically significant and clinically meaningful benefit in PFS vs F in the overall study population, and was well tolerated. The results of SERENA-2 support the further development of C in ER+ HER2- BC. Acknowledgements AstraZeneca sponsored this trial and funded medical writing support from Helen Heffron (InterComm International).

Abstract PD10-08: PD10-08 Immune cell infiltration associated with poor anti-proliferative response to aromatase inhibitors in postmenopausal women with primary ER-positive HER2-negative breast cancer

Abstract Background: Aromatase inhibitors (AIs) are one of the main treatment strategies for the clinical management of estrogen receptor-positive (ER+) breast cancer (BC). Despite prolonged time to recurrence and initial clinical responses, &amp;gt;20% of patients eventually relapse, and previous studies have shown an association of poor anti-proliferative response to AIs and worse outcome. High immune activity in ER+ tumors may be associated with worse outcome, in contrast to ER-negative BC where immune infiltration is a feature associated with better outcome. Our work focused on understanding the correlations between immune cell infiltration and response to AI. Methods: All patients with ER+ HER2- tumors within the bottom 15% of Ki67 anti-proliferative responders to AIs (poor responders [PRs]; n=177) were selected from the PeriOperative Endocrine Therapy for Individualizing Care (POETIC) trial and matched on baseline Ki67 levels to good responders (GRs) within the 50% showing the best response (n=190). Response to AI was measured by the Ki67 percentage change after 2 weeks of treatment. PRs were further divided into groups expressing high ESR1 (PRs ESR1HIGH; n=119) and low ESR1 (PRs ESR1LOW; n=58) levels to represent PR subgroups that showed partial or no response to AIs. The percentage of stromal tumor-infiltrating lymphocytes (TILs) was assessed. Multiple immunofluorescence was performed for ER, CD3, CD20, CD68, FOXP3, and CD3/FOXP3 in 15 baseline samples from each of the GR, PR ESR1HIGH, and PR ESR1LOW populations and immune cell density in stromal or tumor compartments was estimated. Spearman correlations of TILs with Consensus tumor microenvironment (TME) deconvolution and Molecular Signatures Database hallmark gene sets were conducted. The relationship between the immune markers’ density and genes, hallmark gene sets and Consensus TME was assessed. Results: The percentage of TILs was significantly higher in the PR ESR1HIGH and PR ESR1LOW compared to the GRs (adjusted p&amp;lt; 0.05). As expected, TILs were highly correlated with T cells (particularly T-regulatory cells) and immune hallmark gene sets. There was a tendency for higher density of each of the immune markers in PRs compared to GRs, with significant differences being observed in stromal B-cell marker CD20 density (p&amp;lt; 0.05). Analysis showed a significant correlation between TILs and stromal FOXP3 marker density (FDR&amp;lt; 0.05), and stromal biomarker density was highly correlated to the gene expression of the encoding genes of the same tumors (CD3/CD3D, FOXP3/FOXP3, and CD20/MS4A1) (FDRs&amp;lt; 0.05). There was also a strong and significant correlation between the stromal expression of CD20, CD3, FOXP3, and CD3/FOXP3 with the immune hallmark gene sets (FDRs&amp;lt; 0.05). Finally, the immune phenotyping showed the expected correlations with TME deconvolution, with particularly strong correlations of CD20 and CD3 with B- and T-cell gene signatures, respectively (FDRs&amp;lt; 0.05). Conclusions: Different immune features indicated a broad involvement of several immune cell types in PRs to AIs, suggesting that the immune system might be associated with resistance of ER+ breast tumors to AI treatment. Spatial gene expression profiling is ongoing to characterize these tumors further and investigate potential mechanisms of AI resistance. Citation Format: Anastasia Alataki, Gene Schuster, Lila Zabaglo, Perry Maxwell, Elena López-Knowles, Elizabeth Folkerd, David Evans, Kally Sidhu, Holly Tovey, Nicholas Turner, Stephen Johnston, Maggie Chon U Cheang, John Robertson, Manuel Salto-Tellez, Ian Smith, Judith Bliss, Mitch Dowsett. PD10-08 Immune cell infiltration associated with poor anti-proliferative response to aromatase inhibitors in postmenopausal women with primary ER-positive HER2-negative breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD10-08.

Usefulness of 95-gene Signature Assay for ER-positive HER2-negative Early Breast Cancer

Usefulness of 95-gene Signature Assay for ER-positive HER2-negative Early Breast Cancer

Comparison of predicted benefit using RS clin versus observed benefit in a U.S. registry of stage I ER-positive HER2-negative high oncotype DX RS breast cancer.

544 Background: The 21-gene recurrence score assesses the risk of distant breast cancer recurrence and predicts the benefit of adjuvant chemotherapy in ER positive early-stage breast cancer. However, clinicopathologic risk factors continue to impact absolute benefit of adjuvant chemotherapy. Absolute benefit of adjuvant chemotherapy in low clinicopathologic risk Stage I ER positive breast cancer with high Oncotype RS is an important clinical component of shared decision making. The RSClin clinical tool, which integrates the 21-gene recurrence score (RS) and clinicopathologic features, was found to be more prognostic than RS result alone. We assessed RS Clin predicted benefit and compared to absolute benefit in low clinicopathologic risk Stage I ER positive breast cancer with high Oncotype RS as observed in the NCDB. Methods: Using the National Cancer Data Base (NCDB), we identified female patients age 18-75, ER positive and Her 2 negative, 21 gene signature high risk &gt; 25 with negatives surgical margins, &lt;2cm, lymph node negative breast cancers, who had received endocrine therapy with either Tam or AI diagnosed during 2010 - 2017. Clinicopathologic factors and RS were entered into the RSClin calculator, and a predicted benefit of chemotherapy was calculated for each patient. Using NCDB data, Cox proportional hazards regression models were used to project absolute survival benefit at 10 years from diagnosis for those who did vs those who did not receive chemotherapy. NCDB-derived absolute benefit of chemotherapy was compared to estimated absolute benefit as predicted by the RSClin tool. Results: 18,226 patients were identified. Stages T1a = 670(4%), T1b = 4,289(23%), and T1c = 13,267(73%). Median age 59 years (21-75). Race white 84% (15,365), black 10% (1840), and other 1021(6%). AI use 80% (14,711) was greater than Tam use 20% (3515). Chemotherapy was administered in 75% (13,827) of patients. Most patients had high or intermediate grade disease, G3 45% (8225), G2 46% (8328), and G1 9% (1672). Median duration of follow up was 57 months (2-160). Probability of death T1b at 10yrs with chemotherapy was 8.5%, and without chemotherapy was 15.1% with an absolute benefit of 6.6%. Predicted benefit in T1b using RS Clin at 10yrs was 10.8%. Probability of death for T1c at 10yrs with chemotherapy was 15.1%, and without chemotherapy was 23.5% with an absolute benefit of 8.4%. Predicted benefit in T1c using RS Clin at 10yrs was 14%. Conclusions: Patients with stage IB and IC hormone receptor positive HER2 negative breast cancers with high RS had a lower absolute benefit than predicted by RS Clin. The RSClin tool overestimated benefit of therapy in both IB and IC stages requiring caution when using this tool in patients with the lowest clinicopathologic risks.

Short-term preoperative endocrine therapy allows to estimate and revert patient prognosis with further treatment plan correction in HR+ HER2- early breast cancer patients.

e12628 Background: The anomaly function of ER/PR-dependent molecular cascade is a key driver of ER-positive HER2-negative breast cancer (HR+ HER2- BC) progression. Ki67&gt;10% and/or grade 3 (G3) determine the initial poor patient (pts) prognosis in this group. The short-term pre-operative endocrine therapy (P-ET) simply allows to look ahead to properly the further adjuvant therapy (AT) and to estimate the endocrine therapy (ET) sensibility of each pts in the routine clinical practice. The existing diagnostic methods weaknesses for the baseline lymph nodes invasion, high BC heterogeneity do not allow to accurately estimate the disease stage and tumor phenotype, respectively, with 100% accuracy before surgery. In addition to pre-ET the post-operative IHC is a base method for further pts treatment plan especially for high heterogenicity breast tumors. Our study is focused on pts proportion estimation with P-ET benefit or tumor phenotype reversion in patients with early HR+ HER2- BC. Methods: HR+ HER2- BC pts stages I-II any level of Ki67 independent from grade have received P-ET (letrozole (L)/anastrozole (A)/tamoxifen (TAM)) no less than 2 weeks until surgery in MCSC named after A.S. Loginov. Enrollment period runs from Jun’21 and will end with 1,000 pts. The primary goal of the study was pts’s proportion evaluation with baseline Ki67&gt;10% who experienced suppression of the proliferation marker to 10% or less and/or phenotype change during P-ET followed by AT strategy amendment. Results: At the data cut-off (Jan’22) 832 pts (5 pts were men) with HR+ HER2- BC were enrolled (IIT population) with median age 61 (range:26-85) and ECOG 0-2. 736 (89%) pts have baseline Ki67&gt;10% of whom 100 (14%) pts - with G3, 291 (35%) pts - with baseline Ki67≥30%. Tumors of the 398 (54%) pts suppressed proliferation marker Ki67≤ 10% and 352 (88%) pts among them avoid planned adjuvant chemotherapy followed by ET prolongation independent of ET type (L/A/TAM). The median time of P-ET amounted to 39,5 days (range: 14-90) in focused group. Post-operative evaluation of specimens in 20 (2,4%) pts have resulted in the identification of phenotype change to HER2+ BC and TNBC with subsequent modification of AT decisions (including anti-HER2-based and/or dose dense regimens). Conclusions: In HR+ HER2- early BC pts short-term P-ET simply allows to estimate pts prognosis and further AT strategy proper planning: to identify the pts population of whom CT can be avoided while maintaining treatment efficacy with a better quality of life (42% pts of IIT) (1), to radically change the planned AT to achieve optimal treatment results (2,4% pts of IIT) (2).

Conventional and digital Ki67 evaluation and their correlation with molecular prognosis and morphological parameters in luminal breast cancer

Digital counting methods were developed to decrease the high intra- and inter-observer variability of immunohistochemical markers such as Ki67, with most presenting a good correlation coefficient (CC). Since Ki67 is one of the major contributors to Oncotype DX, it is conceivable that Ki67 expression and the recurrence score (RS) obtained by the multigene panel are positively correlated. We decided first to test to what extent conventional and digital Ki67 quantification methods correlate in daily practice and, second, to determine which of these methods correlates better with the prognostic capacity of the Oncotype DX test. Both Ki67 evaluations were performed in 89 core biopsies with a diagnosis of estrogen receptor (ER) positive HER2-negative breast cancer (BC). Cases were, thus, classified twice for surrogate subtype: first by conventional analysis and then by digital evaluation. The Oncotype RS was obtained in 55 cases that were subsequently correlated to Ki67 evaluation by both methods. Conventional and digital Ki67 evaluation showed good concordance and correlation (CC = 0.81 (95% CI 0.73–0.89)). The correlation of Oncotype DX risk groups and surrogate derived subtypes was slightly higher for the digital technique (rs = 0.46, p < 0.01) compared to the conventional method (rs = 0.39, p < 0.01), even though both were statistically significant. In conclusion, we show that digital evaluation could be an alternative to conventional counting, and also has advantages for predicting the risk established by the Oncotype DX test in ER-positive BC. This study also supports the importance of an accurate Ki67 analysis which can influence the decision to submit ER-positive HER2-negative BC to prognostic molecular platforms.

Abstract OT2-19-02: Clinical evaluation of the efficacy and liquid molecular analysis of abemaciclib rechallenge upon progression to abemaciclib combination therapies for ER-positive HER2-negative metastatic breast cancer patients

Abstract Background: Abemaciclib is a drug approved for ER-positive and HER2-negative metastatic or recurrent breast cancer and those treatable in an early setting. Some patients with ER-positive and HER2-negative breast cancer pretreated with abemaciclib and endocrine therapy may still benefit from abemaciclib rechallenge, especially in case of acquired resistance to endocrine therapy. However, there is no evidence for abemaciclib rechallenge. To address this, a single-arm phase 2 trial is planned to determine whether abemaciclib rechallenge has clinical benefits. Translational research to evaluate the gene alteration and immunohistochemistry will be conducted as an accompanying research to determine the predictive biomarkers of resistance or sensitivity to abemaciclib. Patients and Methods: The eligible patients are histologically confirmed with ER-positive and HER2-negative invasive breast cancer, locally advanced or metastatic, and previously received no more than two lines of endocrine therapy. The patients who previously received abemaciclib in combination with endocrine therapy led to a clinical benefit, including complete response, partial response, or stable disease, during abemaciclib-based treatment (≥6 months). The patients who previously received chemotherapy, immune checkpoint inhibitors (excluding perioperative systemic treatment), everolimus, olaparib, and palbociclib for advanced or metastatic diseases are excluded. The patients will be treated with abemaciclib 150 mg orally q12h on days 1 to 28 of a 28-day cycle. The other endocrine drug prescribed was not used in previous treatment. We will evaluate the gene mutations and/or amplification of ESR1, PIK3CA, CCNE1, FGFR1, RB1, TP53, NF1, MYC, AR, and MET at the time of inclusion and three months after day 1 and ctDNA and immunostaining levels of HER3, PTEN, CCNE1, FGFR1/2, and AR at the time of inclusion. The primary endpoint is progression-free survival (PFS), while the secondary endpoints are overall response rate, clinical benefit rate, chemotherapy-free interval, overall survival (OS), safety, and evaluation of the mechanism of sensitivity and resistance to abemaciclib. The expected median PFS for the study treatment arm is 5.0 months compared to the previous data of 3.0 months. The number of necessary cases is 59, with a significance level of 5% (two-sided) and power of 80% during the two-year recruitment period and one-year follow-up period. In the planned total of 65 cases, 10% is considered inappropriate. The planned duration of enrollment and follow-up is two years and one year, respectively. The planned total study duration is four years. Subgroup analysis will be performed on ESR1 and PIK3CA mutations, disease site (visceral/bone only/other), previous lines of therapy for advanced or metastatic disease (first and second), endocrine therapy for pretreatment (aromatase inhibitors/fuluvestrant), performance status (0/1), organs involved (1/2/≥3), age (&amp;lt;65/≥65 years), and disease-free interval (&amp;lt;36 months/≥36 months) to examine the interaction of treatment effects on PFS and OS. This study was funded by Eli Lilly and Company. Citation Format: Meiko Nishimura, Takahiro Kogawa, Yuko Akaishi, Misato Ogata, Jun Masuda, Mitsuo Terada, Hitomi Sakai, Kazuki Nozawa, Sasagu Kurozumi, Takamichi Yokoe, Yukinori Ozaki Ozaki, Shu Yazaki, Mai Onishi, Tsutomu Iwasa, Takuma Onoe, Yuta Okumura, Sayaka Nakayama, Kanako Hagio, Yuko Takahashi, Hirokazu Tanino, Junji Tsurutani, Koji Matsumoto, Mototsugu Shimokawa, Toshimi Takano. Clinical evaluation of the efficacy and liquid molecular analysis of abemaciclib rechallenge upon progression to abemaciclib combination therapies for ER-positive HER2-negative metastatic breast cancer patients [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr OT2-19-02.

Targeting AKT in ER-Positive HER2-Negative Metastatic Breast Cancer: From Molecular Promises to Real Life Pitfalls?

The AKT protein kinase plays a central role in several interconnected molecular pathways involved in growth, apoptosis, angiogenesis, and cell metabolism. It thereby represents a therapeutic target, especially in hormone receptor-positive (HR) breast cancers, where the PI3K/AKT signaling pathway is largely hyperactivated. Moreover, resistance to therapeutic classes, including endocrine therapy, is associated with the constitutive activation of the PI3K/AKT pathway. Improved knowledge on the molecular mechanisms underlying resistance to endocrine therapy has led to the diversification of the therapeutic arsenal, notably with the development of PI3K and mTOR inhibitors, which are currently approved for the treatment of advanced HR-positive breast cancer patients. AKT itself constitutes a novel pharmacological target for which AKT inhibitors have been developed and tested in clinical trials. However, despite its pivotal role in cell survival and anti-apoptotic mechanisms, as well as in endocrine therapy resistance, few drugs have been developed and are available for clinical practice. The scope of the present review is to focus on the pivotal role of AKT in metastatic breast cancer through the analysis of its molecular features and to discuss clinical implications and remaining challenges in the treatment of HR-positive metastatic breast cancer.