Invasive Disease-free Survival Rate Research Articles

Long term safety of controlled ovarian stimulation for fertility preservation prior to chemotherapy treatment in breast cancer patients

ObjectiveTo evaluate the long-term safety of controlled ovarian stimulation for fertility preservation prior to breast cancer chemotherapy treatment DesignRetrospective observational cohort Subjects213 women aged 18-43 years with newly diagnosed stage I-III breast cancer treated with systemic chemotherapy during 2015-2019. Of those, 74 underwent controlled ovarian stimulation for fertility preservation recipients and 141 did not (controls). ExposureControlled ovarian stimulation for fertility preservation Main outcome measuresInvasive disease-free survival, calculated from the time of surgery to the time of detection of breast cancer recurrence or death, whichever came first. ResultsAt diagnosis, fertility preservation recipients were significantly younger than controls (32.7 vs 38.5 years), were less likely to be partnered (44.4% vs 90.1%) or parous (38.9% vs 95%) and were more likely to harbor a BRCA germline mutation (36.5% vs 14.2%). Disease characteristics and treatment modalities were comparable between groups, apart from tumor staging, with maximal tumor diameter being over 5 cm in 22.2% of fertility preservation recipients as opposed to 5.7% of controls (P<0.05). Mean follow-up was 60.9 and 65.4 months for fertility preservation recipients and controls, respectively. 5-year-invasive disease free survival was 80% for fertility preservation recipients and 86% for controls (p=0.20). In a multivariate analysis adjusted for statistically significant covariates, invasive disease free survival remained similar between the groups (Hazards Ratio (HR), 0.86, 95CI 0.4-1.87, p = 0.71). Invasive disease free survival rates were not statistically different in clinically relevant subgroups including patients receiving neoadjuvant chemotherapy (HR 1.57, CI 95 0.62-3.99, p=0.34), and those co-treated with tamoxifen during stimulation due to an ER-positive disease (HR 1.66, 95CI 0.67-3.49, p=0.23). ConclusionsFertility preservation with controlled ovarian stimulation for patients with breast cancer was not found to impair long-term oncologic outcomes, including in emerging clinically relevant subgroups

Predicting invasive disease-free survival in ER-positive, HER2-negative early breast cancer using the PAM50 risk-of-recurrence score: a retrospective analysis using single-center long-term follow-up data of postmenopausal Japanese patients

BackgroundThe prognostic value of the risk-of-recurrence (ROR) score calculated using PAM50 has been validated using clinical trials and patient cohorts. This study aimed to investigate the prognostic value of the PAM50 ROR score in Japanese patients with early breast cancer using long-term follow-up data.MethodsWe enrolled postmenopausal patients with ER-positive, HER2-negative, stage I–II breast cancer who had undergone surgery at the Kyoto University Hospital between 2008 and 2014. The intrinsic subtype and ROR score were calculated using PAM50. The primary endpoint was invasive disease-free survival (IDFS).ResultsWe enrolled 146 patients, of whom 47 (32%) patients had node-positive disease, and 36 (25%) had received neoadjuvant or adjuvant chemotherapy. The proportions of intrinsic subtypes for luminal A, luminal B, HER2-enriched, and basal-like subtypes were 67%, 27%, 3%, and 2%, respectively. The median follow-up duration was 8.4 (range 6.3–10.0) years, and 21 IDFS events were observed. Based on the ROR score, 37%, 33%, and 30% of the patients were classified as low, intermediate, and high risks, respectively. Patients in the high-risk group had a significantly worse 8-year IDFS rate than those in the low-to-intermediate-risk groups (75.1% vs. 91.6%, p = 0.04). The same trend was observed in patients with and without neoadjuvant or adjuvant chemotherapy.ConclusionsUsing long-term follow-up data, this study showed that the ROR score can predict the prognosis of ER-positive, HER2-negative early breast cancer in Japanese postmenopausal patients. Further investigations are required to confirm the prognostic value of the ROR score in Asian populations.

Real-World Study of Adjuvant Biosimilar Trastuzumab-dkst for HER2-Positive Breast Cancer Treatment in a Brazilian Population.

Biological monoclonal antibodies play a pivotal role in cancer treatment, with biosimilars significantly enhancing their accessibility. In Brazil's ethnically diverse setting, real-world evidence is crucial for assessing the effectiveness and applicability of these therapies in routine clinical practice. We performed a multicentric, observational, prospective real-world study on biosimilar trastuzumab-dkst for adjuvant treatment of early HER2-positive breast cancer in Brazilian patients. Data were collected using a case-report form. Of the 176 recruited, we present data from the first 59 patients (mean age 51.7 ± 12.9years) who had completed treatment with trastuzumab-dkst. The mean time from diagnosis to the first adjuvant treatment with trastuzumab-dkst was 5.5 ± 2.7months. Of the patients, 59% of patients achieved at least a 30-month follow-up. The 31.7-month invasive disease-free survival rate (IDFS) was 94.5% (95% CI 83.9-98.2%) and median IDFS was not achieved, since only three patients had invasive disease recurrence. The overall survival rate was 100% until the last assessment. The observed adverse events were similar to those presented by other studies using biosimilar or reference trastuzumab. Four serious adverse events (8.5%) were observed. A reduction in left ventricular ejection fraction of at least 10% was observed in 16.9% of participants. There was no treatment interruption, and three participants (5.1%) had their trastuzumab-dkst dose reduced. Our study reinforces the existing pivotal data, underscoring the real-world efficacy and safety of biosimilar trastuzumab-dkst in the adjuvant treatment for early HER2-positive breast cancer. The preliminary long-term effectiveness and safety data we present further validate trastuzumab-dkst's role as a cost-saving alternative in oncological care. These findings have important implications for improving patient access to crucial treatments and for the more efficient use of healthcare resources. NCT03892655.

Abstract PO3-17-05: Clinical Characteristics and Outcomes of Patients Receiving Adjuvant Paclitaxel and Trastuzumab (APT regimen) for HER2-Positive Early-Stage Breast Cancer in Brazil: A Real-World Evidence

Abstract Introduction: The APT trial established adjuvant paclitaxel and trastuzumab (TH) as the standard of care for HER2-positive early-stage breast cancer with tumor size ≤ 3 cm and no more than one lymph-node micrometastasis. This single-arm phase II trial demonstrated favorable long-term outcomes, with a 3-year invasive disease-free survival (IDFS) rate of 98.7% (95% CI 97.6 – 99.8%). In an updated follow-up analysis, the 10-year IDFS and overall survival (OS) rates were 91.3% (95% CI 88.3 – 94.4%) and 94.3% (95% CI 91.8 – 98.3%), respectively. Nevertheless, outcomes observed in real-world scenarios have frequently been less favorable than those observed in clinical trials. We aimed to characterize the population receiving the APT regimen in clinical practice and evaluate if real-world outcomes align with those observed in the pivotal clinical trial. Methods: This retrospective cohort study included patients with HER2-positive early-stage breast cancer treated between 2015 and 2023 at four Brazilian cancer institutions, including public and private hospitals. Clinical and demographic data, treatment details, and outcomes were collected from electronic records. The primary endpoints were the 3-year and 7-year invasive disease-free survival (IDFS) rates. Secondary endpoints included overall survival (OS) and factors associated with IDFS. Survival analysis employed the Kaplan-Meier method, and Cox regression assessed prognostic factors. Results: A total of 133 patients treated with the APT regimen were evaluated, with a median age of 56 years (range 20–83). The majority had no special type breast carcinoma (92.4%), grade 2 (63.4%) or grade 3 (34.3%) tumors, no angiolymphatic invasion (76.3%), positive estrogen receptor (69.9%), positive progesterone receptor (55.6%), and node-negative disease (94.7%). Tumor staging distribution was as follows: T1a (12%), T1b (23.3%), T1c (49.6%), and T2 (13.5%). Most patients (95.4%) received the APT regimen as per guideline recommendations, while 3.8% received it due to contraindication to other therapies. With a median follow-up of 45.8 months, 8 patients (5.8%) experienced an invasive disease event or death from any cause: 5 (3.8%) had distant recurrence, 1 (0.8%) had local recurrence, and 2 (1.5%) died without recurrence. Notably, these events occurred in patients receiving the APT regimen according to standard indications, except for one patient with N+ disease and a contraindication to another regimen. The recurrence rate according to the T stage is presented in the Table. The 3-year IDFS rate was 100% (95% CI not applicable). All events occurred after the 3-year time point, resulting in a 7-year DFS rate of 80.8% (95% CI 62.7–90.7%). No prognostic factors related to IDFS were identified. Four patients died during the study period, yielding a 7-year OS rate of 88.0% (95% CI 61.6–96.6%). Conclusion: While the baseline characteristics of this cohort resembled those of the APT trial, the long-term outcomes observed in the real-world setting were less favorable. Further investigation is required to determine the reasons for this discrepancy, underscoring the necessity for larger real-world data studies to validate these findings. Recurrence rate according to T stage XX XX Citation Format: Giselle Carvalho, Renata Colombo Bonadio, Pedro Bergmann, Marina Nishimuni, André Rossi, Cristiano Souza, Gabriel Guimarães, Laura Testa, José Bines. Clinical Characteristics and Outcomes of Patients Receiving Adjuvant Paclitaxel and Trastuzumab (APT regimen) for HER2-Positive Early-Stage Breast Cancer in Brazil: A Real-World Evidence [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 PO3-17-05.

Abstract PO3-17-11: The Utility of Oncotype DX in Grade 1 Hormone Receptor-Positive Early Breast Cancer: Insights from a Multicentric Real-World Data Study

Abstract Background: The Oncotype Dx (ODX) genomic risk score (RS) has become an essential tool in clinical practice for guiding adjuvant chemotherapy decisions in early-stage hormone receptor-positive (HR+), HER2-negative breast cancer (BC). Since some of the genes evaluated in the genomic RS tests are proliferation-related, the use of the test is less clear in tumors with low proliferation, such as histologic grade 1 tumors or those with a low Ki67-index. In contrast to common understanding, however, ODX RS is determined more strongly by estrogen-related features and only weakly by proliferation markers. Methods: This multicentric real-world data (RWD) study aimed to evaluate the usefulness of (ODX) in patients with grade 1 (G1) HR+, HER2-negative BC. The study population consisted of patients treated between 2009 and 2020 across nine Brazilian cancer centers. Key endpoints included the prevalence of high genomic RS in the histologic grade 1 cohort, recurrence rates based on genomic risk, and invasive disease-free survival (IDFS). Results: A total of 651 patients with HR+, HER2-negative BC who underwent Oncotype Dx testing were evaluated. Among 651 patients evaluated, 128 had HG1 tumors, constituting the focus of this analysis. The majority of patients were aged over 50 years (59.4%), had breast carcinoma of non-special type (75.8%), and Ki67 index lower than 20% (77%). Tumor stage distribution revealed 28.1% T1b, 50% T1c, and 14% T2 cases. Additionally, 74.2% were classified as N0, 9.4% as N1mic, and 16.4% as N1. According to the binary categorization based on Adjuvant! algorithm, 92.2% of patients (n=118) had a low clinical risk. ODx analysis showed that 21.9% had a low RS, 74.2% had an intermediate RS, and only 3.1% had a high RS. Among the few patients with a high genomic RS, only one patient did not receive adjuvant chemotherapy. With a median follow-up of 38.3 months, three patients experienced recurrence, all of whom had an intermediate RS. Among these cases, two patients were younger than 50 years, had low clinical risk, and a genomic RS of 18-24; both had locoregional recurrences. The third patient, aged over 50 years, had high clinical risk, a RS of 12, and had a distant recurrence. The recurrence rates according to Ki67 index were 1.1% for patients with Ki67 index &amp;lt; 20% and 7.1% for those with Ki67 index ≥ 20%. Notably, no recurrences were observed in the high genomic risk group. The estimated 5-year IDFS rate was 96.9% (95% CI 88.2% - 99.2%). Conclusion: In the context of G1 BC and low clinical risk, the utility and cost-effectiveness of ODX may be limited. These findings emphasize the importance of carefully assessing clinical risk when selecting patients for genomic RS tests, thereby optimizing resource utilization. Longer follow-up is planned for this RWD cohort. Citation Format: Renata Colombo Bonadio, Leandro Oliveira, Daniel Batista, Daniela Rosa, Artur Katz, Max Mano, Daniele Assad-Suzuki, Daniel Argolo, Solange Sanches, Rafael Kaliks, Débora Gagliato, Thais Megid, Daniel Musse, Tatiana Correa, Andrea Shimada, Romualdo Barroso-Sousa, Marcelle Cesca, Débora Gaudêncio, Larissa Moura, Julio Araujo, José Bines, Laura Testa. The Utility of Oncotype DX in Grade 1 Hormone Receptor-Positive Early Breast Cancer: Insights from a Multicentric Real-World Data Study [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 PO3-17-11.

Abstract GS03-12: Phase III study of adjuvant ado-trastuzumab emtansine vs trastuzumab for residual invasive HER2-positive early breast cancer after neoadjuvant chemotherapy and HER2-targeted therapy: KATHERINE final IDFS and updated OS analysis

Abstract Background: Patients with HER2-positive early breast cancer (EBC) who have residual invasive disease after neoadjuvant chemotherapy + HER2-targeted therapy have a high risk of recurrence and death. The standard of care when KATHERINE was designed was continuation of the same HER2-targeted therapy in the adjuvant setting for 1 year. The primary analysis of KATHERINE in 2018 showed that the risk of recurrence of invasive BC or death was 50% lower with adjuvant ado-trastuzumab emtansine (T-DM1) than with trastuzumab. Methods: KATHERINE (NCT01772472/BO27938/NSABP B-50-I/GBG 77) is a phase III, open-label, global study of patients with centrally confirmed, HER2-positive (immunohistochemistry 3+ or in situ hybridization-positive) primary BC (T1–4, N0–3, M0) who received neoadjuvant chemotherapy + HER2-targeted therapy, which had to include a taxane and trastuzumab, followed by surgery, with pathologically documented residual invasive disease in the breast and/or axillary lymph nodes. Within 12 weeks of surgery, patients were randomized 1:1 to T-DM1 (3.6 mg/kg intravenously [IV] every 3 weeks [q3w]) or trastuzumab (6 mg/kg IV q3w) for 14 cycles. Randomization was stratified by clinical stage at presentation, hormone receptor status, single vs dual neoadjuvant HER2-targeted therapy, and pathologic nodal status after neoadjuvant therapy. Patients received radiotherapy and/or endocrine therapy per local standards. The primary endpoint was invasive disease-free survival (IDFS). We report the final IDFS analysis, which was to occur after ~384 events had been reported, and the preplanned second interim analysis of overall survival (OS); specified to occur at the same time. Results: With a median follow-up of 8.4 years (101 months), T-DM1 sustained the improvement in IDFS over trastuzumab (unstratified hazard ratio [HR] 0.54; 95% confidence interval [CI] = 0.44, 0.66; p &amp;lt; 0.0001). Landmark 7-year IDFS rates were increased from 67.1% with trastuzumab to 80.8% with T-DM1; a difference of 13.7%. At clinical cutoff for the final IDFS analysis, 215 deaths had been reported. T-DM1 significantly reduced the risk of death by 34% compared with trastuzumab (unstratified HR 0.66; 95% CI = 0.51, 0.87; p = 0.0027). Deaths had occurred in 89/743 patients (12.0%) in the T-DM1 arm and 126/743 (17.0%) in the trastuzumab arm. Landmark 7-year OS rates were increased from 84.4% with trastuzumab to 89.1% with T-DM1; a difference of 4.7%. OS and IDFS benefits were seen across key subgroups. A low incidence of adverse events (AEs) related to study treatment or to study procedures was observed during the post-treatment period: Grade ≥3 related AEs occurred in 3/740 patients (0.4%) in the T-DM1 arm and 3/720 (0.4%) in the trastuzumab arm; serious related AEs, in 2/740 (0.3%) and 4/720 (0.6%), respectively. Related AEs classed as “cardiac disorders” were rare in both arms with extended follow-up. Conclusions: After 8.4 years (101 months) median follow-up, T-DM1 significantly improved OS in patients with HER2-positive EBC with residual invasive disease after neoadjuvant therapy. The IDFS benefit of T-DM1 was sustained in the intention-to-treat population with longer follow-up, and no new safety issues emerged. Cardiac toxicity was rare in both arms. T-DM1 is the first therapy to show improved survival post-surgery in patients with HER2-positive EBC with residual invasive disease after neoadjuvant therapy. Follow-up is ongoing for the final OS analysis. Citation Format: Sibylle Loibl, Max Mano, Michael Untch, Chiun-Shen Huang, Eleftherios Mamounas, Norman Wolmark, Adam Knott, Asna Siddiqui, Thomas Boulet, Beatrice Nyawira, Eleonora Restuccia, Charles Geyer. Phase III study of adjuvant ado-trastuzumab emtansine vs trastuzumab for residual invasive HER2-positive early breast cancer after neoadjuvant chemotherapy and HER2-targeted therapy: KATHERINE final IDFS and updated OS analysis [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 GS03-12.

Comparison of long-term outcome between clinically high risk lobular versus ductal breast cancer: a propensity score matched study

Abemaciclib is currently approved for the adjuvant treatment of high-risk, lymph node (LN)-positive, hormone receptor (HR)-positive breast cancer (BC). In a real-world setting the clinicopathologic features of patients potentially eligible for adjuvant abemaciclib remain to be defined. There are conflicting data regarding the biological behavior and long-term outcomes across invasive lobular carcinoma (ILC) and invasive ductal carcinoma (IDC). In our study we retrospectively assessed the real-world data and long-term outcome of selected high-risk features ILC compared to IDC, according to the MonarchE trial inclusion criteria. We identified 15,071 patients who got surgery at the European Institute of Oncology for a first primary, non-metastatic, HR-positive, HER2-negative BC from 2000 to 2008. 11,981 (79.5%) patients had an IDC and 1524 (10.1%) an ILC. The remaining 1566 patients (10.4%) had either combined ductal and lobular breast cancer or another histological breast cancer subtype. According to the eligibility criteria of the MonarchE study, we identified two high-risk groups, based on high number of positive lymph nodes, large tumor size, or a high cellular proliferation as measured by tumor grade or biomarkers. Patients were matched by propensity score. A total of 2872 (21.3%) patients were selected as clinically high-risk, including 361/1524 ILC (23.7%) and 2511/11,981 IDC (21%). 322 high-risk ILC were matched with similar high-risk IDC. The median follow-up was 13.2 years for survival. In the matched set, invasive disease-free survival (IDFS) (log-rank P=0.09) and overall survival (OS) (log-rank P=0.48) were not statistically significantly different between the two histological groups. For IDC patients, the 5-year and 10-year IDFS rates (95% CI) were 77.7% (72.9-82.2) and 57.3% (51.7-63.1) respectively, compared to the 5-year and 10-year IDFS rates of ILC patients that were 75.5% (70.6-80.2) and 50.7% (45.0-56.6). The 5-year and 10-year distant relapse free survival (DRFS) rates were 80% (75.3-84.2) and65.3% (59.8-70.7) in IDC cohort, compared to the 5-year and the 10-year DRFS rates of 78.7% (74.0-83.1) and 61.5% (55.9-67.1) in the ILC cohort. Such data match the recent outcomes efficacy results of the MonarchE control arm. More patients in the ILC (n=17) than in the IDC group (n=10) developed axillary recurrence. At multivariable analysis, stratified for specific clinical features, age <35 years, pT2-3, axillary involvement with more than 10 positive axillary nodes were found to be predictors of unfavorable IDFS and OS in the overall matched high-risk population. Findings from this matched cohort study reported similar IDFS and DRFS rates for high risk HR positive early BC when compared to the control arm overall IDFS and DRFS rates reported from the MonarchE trial. Our study demonstrated rates of concordant long-term outcome status beyond histologic subtype. These data support an escalation strategy for these two different histological entities when diagnosed with high-risk features. In our dataset approximately 21% rate of high-risk HR positive early BC patients are potentially eligible for adjuvant abemaciclib treatment. Umberto VeronesiFoundation.

Prognostic factors and benefit populations of ovarian function suppression in premenopausal HR+/HER2+ early-stage breast cancer patients who received trastuzumab: Evidence from a real-world study with long-term follow-up.

Hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-positive (HER2+) breast cancer exhibits considerable heterogeneity, and it is of great interest whether patients with premenopausal HR+/HER2+ breast cancer treated with trastuzumab can benefit from ovarian function suppression (OFS) therapy similarly to HR+/HER2- breast cancer. Here, we conducted a real-world study in this population to identify both who would derive substantial benefits from the addition of OFS and clinicopathological factors with potential prognostic value. Multicenter data from 253 premenopausal patients with HR+/HER2+ early-stage breast cancer who received trastuzumab from October 2009 to October 2018 were retrospectively included. The Kaplan-Meier method was used for survival analysis, while the log-rank test was used to compare the survival rates. Univariate and multifactor Cox regression analyses were performed to analyze the independent risk factors affecting invasive disease-free survival (IDFS). After a median follow-up of 98.50 months, compared with tamoxifen/toremifene alone, tamoxifen/toremifene/aromatase inhibitors plus OFS demonstrated significant benefits in the overall study population (HR = 0.289, 95% CI: 0.100-0.835, p = 0.022, 8-year IDFS rate: 90.78% vs. 95.54%), especially in the lymph node-positive subgroup and age ≤40 years subgroup. Age ≤40 years, histological grade >2, lymph node involvement, PR ≤50%, and tamoxifen alone were independent prognostic factors. For premenopausal HR+ breast cancer patients, HER2 positivity alone is an indication for the addition of OFS in adjuvant endocrine therapy. Age, histological grade, lymph node status, the expression of PR, and OFS treatment were independent prognostic factors in this population.

Abemaciclib combined with endocrine therapy as adjuvant treatment for hormone-receptor-positive, HER2-, high-risk early breast cancer: 5-year Chinese population analysis of the phase III randomized monarchE study.

Abemaciclib was the first cyclin-dependent kinase 4/6 (CDK4/6) inhibitor approved globally in the adjuvant setting for high-risk hormone-receptor positive (HR+)/human epidermal growth factor 2 negative (HER2-) early breast cancer (EBC), based on the phase III monarchE trial. To report an exploratory Chinese population analysis based on the preplanned overall survival (OS) interim analysis with 5-year efficacy results of monarchE. Patients with HR+/HER2-, high-risk (⩾4 positive lymph nodes, or 1-3 nodes and either tumor size ⩾5 cm, histologic grade 3, or Ki-67 ⩾20%) EBC were randomized (1:1) to abemaciclib (150 mg twice daily for 2 years) plus endocrine therapy (ET), or ET alone. This analysis included Chinese patients enrolled in mainland China, Hong Kong, and Taiwan. The primary endpoint was invasive disease-free survival (IDFS); key secondary endpoints included distant relapse-free survival (DRFS), safety, and patient-reported outcomes (PROs). Overall, 501 Chinese patients were included (abemaciclib + ET, n = 259; ET, n = 242). With a median follow-up of 53 months, the addition of abemaciclib to ET resulted in improvements in IDFS (estimated 5-year IDFS rate: 85.9% vs 79.1%; hazard ratio (HR), 0.65 (95% confidence interval (CI) 0.41-1.03)) and DRFS (estimated 5-year DRFS rate: 88.4% vs 82.3%; HR, 0.65 (95% CI, 0.39-1.07)). The most common grade ⩾3 treatment-emergent adverse events in the abemaciclib + ET versus ET groups were neutropenia (24.7% vs 0.8%) and leukopenia (22.4% vs 0.4%). Generally, no clinically meaningful difference in PROs (endocrine symptoms and fatigue) was observed between groups, except for diarrhea. At this prespecified OS interim analysis, which provides 5-year data, the addition of abemaciclib to ET in Chinese patients with high-risk HR+, HER2- EBC was associated with sustained and clinically meaningful improvements in IDFS and DRFS, with acceptable safety and tolerability profiles and minimal impact on PROs. These results represent the first full report of a CDK4/6 inhibitor in Chinese patients with EBC and support the positive benefit-risk profile of adjuvant abemaciclib + ET in Chinese patients. ClinicalTrials.gov identifier: NCT03155997 (first posted: May 16, 2017).

Artículo traducido] Abemaciclib en adyuvancia para el tratamiento del cáncer de mama precoz de alto riesgo

ObjectiveTo adapt the GHEMA report of abemaciclib, an inhibitor of cyclin-dependent kinases 4 and 6. European Medicines Agency authorisation (April 2022) includes, in combination with endocrine therapy, the adjuvant treatment of adult patients with hormone receptor positive, human epidermal growth factor receptor 2 negative, node-positive, early breast cancer at high risk of recurrence. MethodThe efficacy and safety of abemaciclib were evaluated in a randomized, open-label and multicenter phase III study. A total of 5,637 patients diagnosed with early breast cancer with hormone receptor positive, human epidermal growth factor receptor 2 negative, node positive and high risk of recurrence were included. High risk was defined as patients with 4 or more positive axillary lymph nodes, or 1-3positive axillary lymph nodes and at least one of the following: tumor size ≥5 cm, histologic grade 3 or Ki-67 ≥ 20%. Patients were randomized (1:1) to receive adjuvant abemaciclib + endocrine therapy (n = 2,808) or endocrine therapy alone (n = 2,829) for 2 years, with endocrine therapy prescribed for at least 5 years. ResultsWith a median follow-up of 15.5 months, abemaciclib + endocrine therapy demonstrated a statistically significant improvement in invasive disease-free survival versus endocrine therapy alone (HR = 0.747 [95% CI 0.598-0.932], p = 0.0096); achieving an absolute improvement of 3.5% invasive disease-free survival rate at 2-years. These results were maintained, with a median follow-up of 27.7 months: absolute improvement of 2.7% and 5.4% in invasive disease-free survival rate at 2 and 3-years, respectively. All-causality grade 3 or 4 adverse events were 45.9% for abemaciclib and 12.9% for endocrine therapy, and included neutropenia (19.6% vs. 0.8%), leukopenia (11.4% vs. 0.4%) and diarrhea (7.8% vs. 0.2%). ConclusionsThe results of the pivotal trial are sufficient to consider abemaciclib as adjuvant treatment for high-risk early breast cancer in highly selected patients. However, in order to the efficacy results present less uncertainty, we must wait for a evaluation later, in which we can have a mature determination at 3 years (with more patients at risk).

Abemaciclib as adjuvant treatment for high-risk early breast cancer

ObjectiveTo adapt the GHEMA report of abemaciclib, an inhibitor of cyclin-dependent kinases 4 and 6. European Medicines Agency authorization (April 2022) includes, in combination with endocrine therapy, the adjuvant treatment of adult patients with hormone receptor positive, human epidermal growth factor receptor 2 negative, node-positive, early breast cancer at high risk of recurrence. MethodThe efficacy and safety of abemaciclib were evaluated in a randomized, open-label, and multicenter phase III study. A total of 5637 patients diagnosed with early breast cancer with hormone receptor positive, human epidermal growth factor receptor 2 negative, node positive, and high risk of recurrence were included. High risk was defined as patients with 4 or more positive axillary lymph nodes, or 1–3 positive axillary lymph nodes and at least one of the following: tumor size ≥5 cm, histologic grade 3, or Ki-67≥20%. Patients were randomized (1:1) to receive adjuvant abemaciclib+endocrine therapy (n = 2808) or endocrine therapy alone (n = 2829) for 2 years, with endocrine therapy prescribed for at least 5 years. ResultsWith a median follow-up of 15.5 months, abemaciclib+endocrine therapy demonstrated a statistically significant improvement in invasive disease-free survival versus endocrine therapy alone [HR = 0.747 (95% CI 0.598–0.932), P = 0.0096]; achieving an absolute improvement of 3.5% invasive disease-free survival rate at 2-years. These results were maintained, with a median follow-up of 27.7 months: absolute improvement of 2.7% and 5.4% in invasive disease-free survival rate at 2 and 3 years, respectively. All-causality grade 3 or 4 adverse events were 45.9% for abemaciclib and 12.9% for endocrine therapy, and included neutropenia (19.6% vs. 0.8%), leukopenia (11.4% vs. 0.4%), and diarrhea (7.8% vs. 0.2%). ConclusionsThe results of the pivotal trial are sufficient to consider abemaciclib as adjuvant treatment for high-risk early breast cancer in highly selected patients. However, in order to the efficacy results present less uncertainty, we must wait for a evaluation later, in which we can have a mature determination at 3 years (with more patients at risk).

107P Results in Chinese patients from pre-planned overall survival interim analysis in monarchE: Abemaciclib plus adjuvant endocrine therapy for high risk HR+, HER2- early breast cancer

Abemaciclib (oral CDK4 and 6 inhibitor) plus endocrine therapy (ET) as adjuvant treatment demonstrated clinically meaningful improvement in invasive disease-free survival (IDFS) and distant relapse-free survival (DRFS) in Chinese patients (pts) with Hormone Receptor (HR+)-positive and human epidermal growth factor 2 (HER2)-negative high risk early breast cancer (EBC). This combination therapy provided sustained clinical benefits at the pre-planned overall survival interim analysis (OS IA2). Here we present the results of the subset of Chinese patients from monarchE at OS IA2. The overall study design was previously reported. Pts were randomized 1:1 to receive Abemaciclib + ET or ET alone. Eligible pts with ≥4 positive nodes, or 1-3 nodes and Grade 3 disease and/or tumor size ≥5 cm were included in Cohort 1 (C1); pts with 1-3 nodes and central Ki-67 ≥20% who did not meet entry criteria for C1 were included in Cohort 2 (C2). Analyses were conducted in Chinese pts enrolled from Mainland China, Hong Kong, and Taiwan in the intent-to-treat (ITT) population (501 pts), consisting of C1 (440 pts) and C2 (61 pts). At the time of data cutoff (July 1, 2022), all Chinese pts were off treatment with median follow-up of around 41 months. Sustained benefits of IDFS (HR=0.563, 95%CI: 0.343-0.923) and DRFS (HR=0.586, 95%CI: 0.341-1.006) were observed in Chinese pts in the ITT, with clinically meaningful improvement in the 4-year IDFS rates (88.5% vs 79.6%) and DRFS rates (90.0% vs 82.4%). In C1, the HR for IDFS was 0.582 (95%CI: 0.351-0.965) and DRFS was 0.610 (95%CI: 0.350-1.063), and a consistent benefit of abemaciclib was observed regardless of Ki-67 index. There were limited events of deaths in Chinese pts (abemaciclib plus ET vs ET: 6 [2.3%] vs 5 [2.1%]). No new safety signals were observed in Chinese pts. Consistent with reported results for the overall ITT population, abemaciclib combined with ET demonstrated clinically meaningful and sustained IDFS and DRFS benefits among Chinese pts with HR+, HER2-, high risk EBC and continued separation of the IDFS and DRFS curves. The OS data remain immature and follow-up is ongoing.

Abstract GS1-09: Abemaciclib plus endocrine therapy for HR+, HER2-, node-positive, high-risk early breast cancer: results from a pre-planned monarchE overall survival interim analysis, including 4-year efficacy outcomes

Abstract Background Adjuvant abemaciclib (a CDK4 and 6 inhibitor) combined with ET resulted in significant and clinically meaningful improvement in invasive disease-free survival (IDFS) and distant relapse-free survival (DRFS) in patients (pts) with HR+, HER2-, node-positive, high risk EBC in the monarchE trial, and is an approved adjuvant therapy for these patients. Here we present efficacy results from a pre-specified overall survival interim analysis (OS IA2) which was planned to occur 2 years (yrs) after the primary outcome analysis. Methods Pts were randomized (1:1) to receive ET for up to 10 yrs +/- abemaciclib for 2 yrs (study treatment period). High-risk EBC was defined as either ≥4 positive axillary lymph nodes (ALN), or 1-3 ALN with either Grade 3 disease and/or tumor ≥5 cm (Cohort 1). While the proliferation biomarker Ki-67 was centrally assessed in all pts with available tissue sample, an additional smaller group of pts with 1-3+ ALN and central Ki-67 ≥20% as the only high-risk feature were included (Cohort 2). The intent-to-treat (ITT) population consisted of both Cohort 1 (5120 pts) and Cohort 2 (517 pts). Hazard ratios (HR) were estimated using Cox proportional hazard model. Results At a median follow-up of 42 months, all pts were off abemaciclib. IDFS and DRFS data illustrate a sustained benefit beyond the treatment period. In the ITT population, the HR for IDFS was 0.664 (95% CI: 0.578, 0.762) and DRFS was 0.659 (95% CI: 0.567, 0.767). At 4 yrs, this reflected an improvement in IDFS rates from 79.4% to 85.8% (absolute difference 6.4%), and in DRFS rates from 82.5% to 88.4% (absolute difference 5.9%). The continued separation of the curves was associated with an increase in absolute benefit in IDFS 4-year rates compared to 2-and 3-year IDFS rates (absolute difference 2.8% and 4.8% respectively). While OS remained immature, there was a lower number of deaths observed in the abemaciclib plus ET arm compared to the ET alone arm (157 [5.6%] vs 173 [6.1%], HR 0.929 [95% CI: 0.748, 1.153], p = 0.503), suggesting that the robust benefit in IDFS and DRFS began to translate into a numerically favorable OS HR. As previously described, within Cohort 1, a Ki-67 index of ≥20% was associated with a worse prognosis, but similar abemaciclib treatment effects were observed regardless of Ki-67 index. No new safety signals were observed. Conclusion The clinically meaningful benefit of adjuvant abemaciclib added to ET in HR+, HER2-, node-positive, high-risk EBC persists beyond completion of abemaciclib therapy, yielding an increase in absolute IDFS and DRFS benefit at 4 yrs. While OS remains immature at this time, the lower number of deaths in the abemaciclib arm compared to the ET arm suggest that a survival signal favoring abemaciclib is emerging. Citation Format: Stephen Johnston, Masakazu Toi, Joyce O’Shaughnessy, Priya Rastogi, Mario Campone, Patrick Neven, Chiun Sheng Huang, Jens Huober, Georgina Garnica Jaliffe, Irfan Cicin, Sara Tolaney, Matthew P. Goetz, Hope Rugo, Elżbieta Senkus, Laura Testa, Lucia Del Mastro, Chikako Shimizu, Ran Wei, Ashwin Shahir, Maria Munoz, Belen San Antonio, Valerie Andre, Nadia Harbeck, Miguel Martín. Abemaciclib plus endocrine therapy for HR+, HER2-, node-positive, high-risk early breast cancer: results from a pre-planned monarchE overall survival interim analysis, including 4-year efficacy outcomes [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 GS1-09.

VP8-2021: Adjuvant abemaciclib combined with endocrine therapy (ET): Updated results from monarchE

Adjuvant abemaciclib (CDK4 & 6 inhibitor) combined with ET provides significant and clinically meaningful improvement in invasive disease-free survival (IDFS) and distant relapse-free survival (DRFS) in patients (pts) with HR+, HER2-, node-positive, high risk early breast cancer (EBC). Updated results with a median follow-up of 27 months are presented. Pts were randomized (1:1) to receive ET for up to 10 years (yrs) +/- abemaciclib for 2 yrs. Pts had ≥4+ axillary lymph nodes (ALN), or 1-3+ ALN and either grade 3 disease or tumor ≥5 cm (Cohort 1), or 1-3+ ALN and centrally tested Ki-67 ≥20% (Cohort 2). For the ITT (cohort 1+2) and Ki-67 populations, hazard ratio (HR) was estimated using Cox proportional hazard model (data cutoff 1 April 2021). Exploratory analyses estimated the piecewise HR within each yr in the ITT. With 90% of pts having completed or discontinued the 2-yr study treatment period, the magnitude of IDFS benefit deepened (HR=0.696, 95% CI=0.588, 0.823; nominal p<0.0001) and DRFS benefit was maintained (HR=0.687, 95% CI=0.571, 0.826; nominal p<0.0001). At 3 yrs, absolute improvement in IDFS and DRFS rates were 5.4% and 4.2%, respectively. Abemaciclib benefit deepened during the treatment period (estimated IDFS/DRFS piecewise HRs at yr 0-1 0.795/0.732, yr 1-2 0.681/0.675) and persisted after the 2-yr treatment period (2+ yr IDFS/DRFS piecewise HRs 0.596/0.692). Estimated IDFS rates in the control arm of Cohort 1 (Ki-67 High vs Low) confirmed the prognostic value of Ki-67; however, abemaciclib benefit was consistent regardless of Ki-67 index (table). Overall, AE profile was similar to the prior analysis.Table: VP8-2021IDFSDRFSAbemaciclib + ETETHR (95% CI)Abemaciclib + ETETHR (95% CI)ITT (Cohort 1+2), N = 5637 Patients, N280828290.696 (0.588, 0.823)280828290.687 (0.571, 0.826) Events, n232333191278 3-Year Rates88.8%83.4%90.3%86.1%Ki-67 High (Cohort 1+2), N = 2498 Patients, N126212360.663 (0.524, 0.839)126212360.639 (0.494, 0.827) Events, n11817297146 3-Year Rates86.8%80.8%88.3%84.3%Cohort 1-Ki-67 High, N = 2003 Patients, N10179860.626 (0.488, 0.803)10179860.599 (0.456, 0.787) Events, n10415885135 3-Year Rates86.1%79.0%87.8%82.6%Cohort 1-Ki-67 Low, N = 1914 Patients, N9469680.704 (0.506, 0.979)9469680.679 (0.473, 0.975) Events, n62865073 3-Year Rates91.7%87.2%93.1%89.1% Open table in a new tab The benefit of adjuvant abemaciclib added to ET is strengthened within and beyond the 2-yr treatment period for pts with HR+, HER2-, node-positive, high risk EBC. High Ki-67 was prognostic, but not predictive of abemaciclib benefit. Safety profile remains acceptable for pts with EBC treated with curative intent.

Efficacy and safety analysis of Chinese patients in monarchE: Abemaciclib combined with adjuvant endocrine therapy for high risk HR+, HER2- early breast cancer.

522 Background: In monarchE, abemaciclib (oral CDK4&amp;6 inhibitor) plus endocrine therapy (ET) as adjuvant treatment for HR+, HER2- high risk early breast cancer (EBC), demonstrated a statistically significant improvement in invasive disease-free survival (IDFS) compared to ET alone. Here we present the efficacy and safety analysis of Chinese patients from monarchE. Methods: The overall study design was reported previously. Eligible patients were randomized to receive abemaciclib (150 mg BID for 2 years) combined with standard adjuvant ET or ET alone. The primary endpoint was IDFS per STEEP criteria. Secondary endpoints included distant relapse-free survival (DRFS), overall survival, and safety. Exploratory subgroup analyses were conducted among Chinese patients enrolled from Mainland China, Hong Kong, and Taiwan in the intent-to-treat (ITT) population. Results: A total of 501 Chinese patients were randomized to receive abemaciclib plus ET (259 patients) or ET alone (242 patients). At the time of data cutoff (July 8, 2020), 356 (71.1%) patients were still in the 2-year treatment period. A total of 26 IDFS events were observed (11 and 15 events in abemaciclib plus ET and ET arm, respectively). Comparing to ET alone, abemaciclib combined with ET reduced the risk of developing invasive disease or death by 34.3% (HR: 0.657, 95% CI: 0.301, 1.435) for Chinese patients, together with a clinically meaningful improvement in the 2-year IDFS rate (95.6% vs 92.1%). The addition of abemaciclib to ET also resulted in an improvement in DRFS (HR: 0.601, 95% CI: 0.245, 1.477) for Chinese patients, with the 2-year DRFS rate at 96.7% (ET alone: 93.4%). In the abemaciclib arm, the most frequent treatment-emergent adverse events (TEAEs) and grade ≥3 TEAEs: diarrhea (90.3% and 5.0%), leukopenia (76.8% and 21.2%), and neutropenia (76.4% and 23.9%), respectively. Conclusions: Abemaciclib combined with adjuvant ET demonstrated clinically meaningful IDFS and DRFS benefits among Chinese patients with HR+, HER2-, high risk EBC, which was consistent with the ITT population as reported previously. The safety profile of abemaciclib in Chinese EBC patients was consistent with global population and also with that observed in Chinese metastatic breast cancer patients. Clinical trial information: NCT03155997.

Recurrence risk in early breast cancer as defined by clinicopathologic features.

e18581 Background: While most patients (pts) with HR+, HER2- early breast cancer (EBC) do not experience disease recurrence, those with high risk clinicopathologic features may have recurrence within the first few years on adjuvant endocrine therapy (AET). This study estimates risk of recurrence in pts with EBC based on clinicopathologic features and evaluates the medical need for more efficacious treatments using US oncology practice data. Methods: This retrospective study used the nationwide Flatiron Health electronic health record derived deidentified database. The cohort included pts with HR+, HER2- stage I-III breast cancer, diagnosed Jan 2011-Mar 2020, who received surgery and AET. Clinicopathologic features were used to identify a ‘high risk (HiR) group’ (≥ 4 positive axillary lymph nodes (LN), or 1-3 positive axillary LN and ≥ 1 of the following: Grade 3, tumor size ≥ 5 cm, or Ki-67 ≥ 20%) and ‘low risk (LoR) group’ (pts who do not meet above criteria, including a subset with node negative (N0) disease). Cox proportional hazards regression models compared invasive disease-free survival (IDFS) and distant relapse-free survival (DRFS) from AET initiation between groups according to a sequential gatekeeping strategy and stepwise analysis: first compare HiR group to N0 pts; if significant then compare HiR to LoR group. Results: 557 (13.8%) pts were in the HiR group and 3,471 (86.2%) in the LoR group (including 2,867 N0 pts). The study population (median age 64 yrs) was predominantly female (99.2%), white (69.4%) and postmenopausal (75.6%) with median follow-up of 39.6 months. Pts in the HiR group were younger and more likely premenopausal, have a BRCA mutation, invasive lobular carcinoma and less likely to have received an Oncotype DX test compared to LoR pts. Of the 557 HiR pts, 231 (41.5%) had ≥ 4 positive LN and 326 (58.5%) had 1-3 positive axillary LN with additional risk factor(s): tumor size ≥ 5 cm (11.7%), histologic grade 3 (32.0%), and/or Ki-67 ≥ 20% (31.6%). Most HiR pts received radiotherapy (82.4%) and chemotherapy (68.1%). Significant differences in IDFS and DRFS were observed between HiR group and N0 and LoR groups (logrank test p &lt; .0001 for all). The 2-year IDFS rate was 88.1% in the HiR group, compared to 97.4% in N0 pts and 97.1% in the LoR group; 2-year DRFS rates were 89.0% compared to 97.9% and 97.7%, respectively. Pts in the HiR group had significantly higher hazard of invasive disease recurrence or death compared to N0 (HR = 3.42, 95% CI: 2.69-4.34, p &lt; .0001) and LoR group (HR = 3.07, 95% CI: 2.46-3.84, p &lt; .0001). Similar results observed for DRFS (HiR vs N0: HR = 3.46, 95% CI: 2.70-4.44, p &lt; .0001; HiR vs LoR HR = 3.16, 95% CI: 2.50-3.98, p &lt; .0001). Conclusions: Approximately 12% of pts with EBC and high risk clinicopathologic features experienced invasive disease recurrence or death within 2 years of initiating AET. Optimal use of standard therapies and novel treatment options are needed to prevent early recurrence and metastases in these pts.

Abemaciclib combined with adjuvant endocrine therapy in patients with high risk early breast cancer who received neoadjuvant chemotherapy (NAC).

517 Background: monarchE, a phase 3, open-label, randomized study evaluating abemaciclib combined with adjuvant endocrine therapy (ET) compared to ET alone in patients with HR+, HER2-, high risk early breast cancer (EBC), resulted in a statistically significant improvement in invasive disease-free survival (IDFS) (HR = 0.713; 95% CI: 0.583, 0.871). NAC is used in patients with HR+, HER2- EBC at higher risk of recurrence despite often limited response, suggesting a need for enhanced adjuvant ET. Methods: Patients with ≥4 positive notes (LNS), or 1-3 LNS and either Grade 3 disease, tumor size ≥5 cm, or central Ki-67 ≥20% were eligible. Prior chemotherapy (NAC, adjuvant, none) was one of the stratifications factors. Prior therapy and tumor characteristics prior to study entry were collected. Here, we present the results of the prespecified subgroup of patients who received NAC. Results: Out of 5,637 randomized patients, 2056 (36.5%) received NAC. For 84.8%, the chosen regimen included anthracycline + cyclophosphamide + taxane, for 4.4%, it included anthracycline + taxane. A total of 1044 (50.8%) patients who received NAC had a radiologic tumor size between 2-5 cm and 599 (29.1%) had tumors ≥5 cm at diagnosis. 6.2%, 49.4% and 36.7% of patients had tumors with histologic Grade 1, 2, 3 respectively. 55.2% of patients had LNS ≥4+ and 44.4% had 1-3+ LNS. Central Ki-67 prior to NAC was ≥20% in 64.8% of patients with available Ki-67 results (664 (32.3%) patients had missing Ki-67 results). Evaluation of clinical and pathological measures of response will be presented. A multivariate cox regression analysis of IDFS in the intent-to-treat (ITT) population, identified prior chemotherapy as prognostic, suggesting patients who received NAC were at risk of a worse outcome. Primary outcome efficacy data for patients who received NAC are shown in the table below. Abemaciclib + ET demonstrated treatment benefit in terms of IDFS vs ET alone (HR: 0.614 95% CI: 0.473, 0.797) with 2-year IDFS rates of 87.2% vs 80.6%, respectively. The addition of abemaciclib to ET resulted in an improvement in distant relapse-free survival (DRFS) (HR: 0.609, 95% CI: 0.459, 0.809), with 2-year DRFS rates of 89.5% and 82.8%, respectively. Safety profile was similar to the overall safety population. Conclusions: Patients with HR+, HER2- EBC who received NAC were noted to be at a higher risk of recurrence. In this subgroup, abemaciclib combined with ET demonstrated a clinically meaningful treatment benefit in IDFS and DRFS, which was numerically greater than in the ITT population. Safety data were consistent with abemaciclib safety profile. Clinical trial information: NCT03155997. [Table: see text]

Abstract PS4-28: Efficacy of adjuvant chemotherapy stratified by age and the 21 gene recurrence score in estrogen receptor positive breast cancer

Abstract Background: The 21-gene recurrence score (RS) can predict chemotherapy benefit in estrogen receptor (ER)-positive, human epidermal growth factor receptor-2 (HER2)-negative early breast cancer patients. The TAILORx showed that age would influence the interaction between RS and chemotherapy effect, and patients ≤50 years with RS &amp;gt;15 can benefit from chemotherapy. The current study aimed to determine the RS threshold that can predict chemotherapy benefit in both young and elder women. Methods: Patients diagnosed with pN0-1, ER+/HER2- breast cancer between 2009 and 2016 at Shanghai Ruijin hospital were retrospectively reviewed. A one-to-one propensity score matching (PSM) was performed between women receiving chemotherapy or not. Patients were then stratified by different cutoffs of age (range, 30-65 years). In each prespecified strata of age, cox proportional hazards models were used to determine the RS threshold which was predictive of chemotherapy benefit. Results: A total of 1227 patients were included. The median age was 58 years and the median RS was 24. After matching, the RS values that can manifest the chemotherapy benefit varied with age. For patients at 55 years of age or younger, apparent chemotherapy benefit was observed in those who had RS &amp;gt;25 (P = 0.03), with 4-year invasive disease-free survival (IDFS) rate of 97.0% and 89.3% in patients receiving chemotherapy or not. While patients derived no benefit from chemotherapy if they had RS ≤25 (P = 0.66, 4-year IDFS rate: 95.3% vs. 94.6%). However, for patients older than 55 years, adjuvant chemotherapy was associated with better prognosis in those with RS &amp;gt;36 (P = 0.014, 4-year IDFS rate: 94.7% vs. 76.2%), but not in those having RS ≤36 (P = 0.13, 4-year IDFS rate: 92.3% vs. 95.8%). Conclusions: The RS threshold to demonstrate the chemotherapy benefit differed with age. Young patients with RS &amp;gt;25 and old patients with RS &amp;gt;36 could benefit from adjuvant chemotherapy. Survival of breast cancer patients receiving adjuvant chemotherapy or not stratified by age and theChemoendocrine therapyEndocrine therapyP-value4-year IDFS rate (%)95% CI (%)4-year IDFS rate (%)95% CI (%)≤55 yearsRS ≤2595.390.7-100.094.689.6-100.00.66RS &amp;gt;2597.091.3-100.089.382.0-97.30.03&amp;gt;55 yearsRS ≤3692.387.7-97.295.892.1-99.60.13RS &amp;gt;3694.787.9-100.076.252.1-100.00.014 Citation Format: Jing Yu, Caijin Lin, Jiahui Huang, Jin Hong, Weiqi Gao, Siji Zhu, Hui Wang, Ou Huang, Xiaosong Chen, Jianrong He, Li Zhu, Weiguo Chen, Yafen Li, Kunwei Shen, Jiayi Wu. Efficacy of adjuvant chemotherapy stratified by age and the 21 gene recurrence score in estrogen receptor positive breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS4-28.

Abstract PD2-01: High Ki-67 as a biomarker for identifying patients with high risk early breast cancer treated in monarchE

Abstract Background monarchE, a phase 3, open-label, randomized study evaluating endocrine therapy with or without abemaciclib in patients with node positive, HR+, HER2-, high risk early breast cancer, resulted in a statistically significant improvement in invasive disease-free survival (IDFS) at a pre-planned interim analysis. Ki-67, a marker of cellular proliferation in breast cancer, was used in addition to other clinical and/or pathological features to identify patients whose cancer may be at higher risk of recurrence. A key secondary endpoint was to evaluate IDFS in patients with high (≥20%) Ki-67 tumors. Methods Patients with ≥4 positive nodes, or 1-3 nodes and either grade 3 disease, tumor size ≥5 cm, or central Ki-67 ≥20% were eligible for monarchE. Ki-67 was centrally assessed for all eligible patients with suitable untreated breast tissue using a standardized kit produced by Agilent/Dako (MIB-1). A sequential gatekeeping strategy was utilized to test the statistical significance in IDFS for patients with high Ki-67 tumors. Data on this subgroup are presented. Results Primary outcome results in the ITT population are presented separately and resulted in a significant 28.7% reduction in the risk of developing invasive disease with abemaciclib plus ET versus ET alone (HR = 0.713; 95% CI = 0.583, 0.871). Of the 5637 patients enrolled in monarchE, 4425 (78.5%) had Ki-67 samples eligible for testing. Of those tested, 2498 patients (56.5%) had Ki-67 ≥20% (Ki-67H). Results from the Ki-67H population are presented separately and showed that abemaciclib plus ET demonstrated superior IDFS versus ET alone with a 30.9% reduction in the risk of invasive disease (p=.0111; HR = 0.691; 95% CI = 0.519, 0.920). There was an absolute improvement of 4.5% in IDFS rate at 2 years (91.6% in the abemaciclib arm and 87.1% in the control arm). An additional planned analysis was performed evaluating efficacy in 2003 patients with high Ki-67 tumors enrolled in cohort 1 (patients with ≥4 positive nodes or 1-3 nodes and either tumor size ≥5 cm and/or grade 3 disease). The IDFS treatment benefit in this group was statistically significant with a HR of 0.643 (95% CI = 0.475, 0.872) corresponding to a 35.7% reduction in the risk of developing invasive disease. Two-year IDFS rates in this group were 91.3% in the abemaciclib group and 86.1% in the control arm, representing a 5.2% absolute improvement at 2 years. A clinically meaningful improvement was also observed in distant relapse-free survival (DRFS) in both populations. Baseline characteristics were balanced across arms in both Ki-67H populations. An exploratory analysis was conducted evaluating patients in cohort 1 with low Ki-67 (&amp;lt;20%) and will be presented. Conclusion This represents the first time a prespecified threshold of ≥20% for Ki-67 has been used to prospectively evaluate the utility of Ki-67 in a phase III registration trial with a standardized assay. There was a statistically significant improvement in IDFS for patients with high Ki-67 tumors across the ITT population (HR = 0.691) and in cohort 1 (HR = 0.643). These results suggest that Ki-67 ≥20% is an additional clinicopathological feature that can be used in conjunction with high risk features of nodal involvement, tumor size, and grade, to select patients with a higher risk of recurrence who may benefit from treatment with abemaciclib in the adjuvant setting. ClinicalTrials.gov: NCT03155997 Ki-67H Ki-67H Cohort 1EndpointAbemaciclib + ETN=1262ET aloneN=1236Abemaciclib + ETN=1017ET aloneN=986IDFS# events, n (%)82 (6.5)115 (9.3)71 (7.0)106 (10.8)log rank Pvalue, HR (95% CI)p=.0111 0.691 (0.519, 0.920)p=.00420.643 (0.475, 0.872)Rate (%) at 2-years (95% CI)91.6(89.4, 93.4)87.1(84.3, 89.5)91.3(88.9, 93.2)86.1(83.1, 88.7)DRFS# events, n (%)65 (5.2)102 (8.3)56 (5.5)96 (9.7)log rank Pvalue,HR (95% CI)p=.0018 0.609 (0.445, 0.833)p=.00040.554 (0.397, 0.773)Rate (%) at 2 years (95% CI)93.6(91.6, 95.1)88.5(85.7, 90.7)93.3(91.2, 95.0)87.384.4, 89.8) Citation Format: Nadia Harbeck, Stephen Johnston, Peter Fasching, Miguel Martin, Masakazu Toi, Priya Rastogi, Chuangui Song, David Molthrop, Jacqueline Vuky, Toshinari Yamashita, Georgina Garnica Jaliffe, Mahmut Gumus, Desiree Headley, Ran Wei, Susana Barriga, Maria Munoz, Michael Method, Valerie Andre, Hans Kreipe, Joyce O'Shaughnessy. High Ki-67 as a biomarker for identifying patients with high risk early breast cancer treated in monarchE [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD2-01.

Abstract GS1-01: Primary outcome analysis of invasive disease-free survival for monarchE: abemaciclib combined with adjuvant endocrine therapy for high risk early breast cancer

Abstract Background monarchE is a phase 3, open-label study evaluating abemaciclib combined with endocrine therapy (ET) compared to ET alone in patients with node positive, HR+, HER2-, high risk early breast cancer (EBC) that resulted in a statistically significant improvement in invasive disease-free survival (IDFS) at a pre-planned interim analysis. Following the positive interim analysis, patients continued to be followed for IDFS, distant recurrence, and overall survival. Methods After surgery and, as indicated, radiotherapy and/or chemotherapy, 5,637 patients with HR+, HER2-, high risk EBC were randomized (1:1) to standard of care adjuvant ET with or without abemaciclib (150 mg BD for 2 years). Patients with ≥4 positive nodes, or 1-3 nodes and either grade 3 disease, tumor size ≥5 cm, or central Ki-67 ≥20% were eligible. Here we present results of the primary outcome IDFS analysis which was planned after approximately 390 IDFS events. Results At the primary outcome analysis, median follow-up was approximately 19 months in both arms (an increase of 3.5 months from the interim analysis). A total of 1437 (25.5%) patients had completed the 2-year treatment period; 3281 (58.2%) were still in the 2-year treatment period. With 395 IDFS events observed in the intent-to-treat population, abemaciclib plus ET continued to demonstrate superior IDFS versus ET alone, with a 28.7% reduction in the risk of developing invasive disease (p=.0009; HR = 0.713; 95% CI = 0.583, 0.871). Two-year IDFS rates were 92.3% in the abemaciclib plus ET arm and 89.3% in the ET alone arm. There was a consistent benefit of abemaciclib in all prespecified subgroups. The addition of abemaciclib to ET also resulted in an improvement in distant relapse-free survival (DRFS). Overall survival was immature at the time of analysis. A key secondary endpoint was efficacy in patients with centrally assessed high Ki-67 (≥20%) (Ki-67H) (n=2498). Disease characteristics were well balanced between the arms of this population. Abemaciclib plus ET demonstrated superior IDFS vs ET alone, with a 30.9% reduction in risk of developing invasive disease (p=.0111; HR = 0.691; 95% CI = 0.519, 0.920) and 2-year IDFS rates of 91.6% and 87.1%, respectively. An improvement in DRFS treatment effect was also observed in the Ki-67H population. At the time of data cutoff, the median treatment duration of abemaciclib was 17.3 months and the median duration of ET was balanced between the arms (18.3 months in the abemaciclib arm and 18.7 months in the ET alone arm). Safety was consistent with the results at the interim IDFS analysis and with the known safety profile of abemaciclib. Conclusions At the primary outcome analysis, with a median follow-up of approximately 19 months, abemaciclib combined with ET continued to demonstrate a clinically meaningful improvement in IDFS in patients with HR+, HER2-, node-positive, high risk, EBC with a statistically significant improvement in IDFS in patients with central Ki-67 ≥20%. ClinicalTrials.gov: NCT03155997 Table 1: PrimaryOutcome EfficacyIntent-to-Treat PopulationIntent-to-Treat PopulationKi-67 ≥20% (Ki-67H) PopulationKi-67 ≥20% (Ki-67H) PopulationEndpointAbemaciclib + ET N=2808ET alone N=2829Abemaciclib + ET N=1262ET alone N=1236IDFS# events, n (%)163 (5.8)232 (8.2)82 (6.5)115 (9.3)log rank P value, HR (95% CI)p=.0009 0.713 (0.583, 0.871)p=.0111 0.691 (0.519, 0.920)Rate (%) at 2 years (95% CI)92.3 (90.9, 93.5)89.3 (87.7, 90.7)91.6 (89.4, 93.4)87.1 (84.3, 89.5)Difference (%) in 2-year rates (95% CI)3 (1.1, 5.0)4.5 (1.2, 7.7)DRFS# events, n (%)131 (4.7)193 (6.8)65 (5.2)102 (8.3)log rank P value, HR (95% CI)p=.0009 0.687 (0.551, 0.858)0.609 (0.445, 0.833)Rate (%) at 2 years (95% CI)93.8 (92.6, 94.9)90.8 (89.3, 92.1)93.6 (91.6, 95.1)88.5 (85.7, 90.7)Difference (%) in 2-year rates (95%CI)3 (1.2, 4.8)5.1 (2.1, 8.1) Citation Format: Joyce A. O'Shaughnessy, Stephen Johnston, Nadia Harbeck, Masakazu Toi, Young-Hyuck Im, Mattea Reinisch, Zhimin Shao, Pirkko Liisa Kellokumpu Lehtinen, Chiun-Sheng Huang, Alexey Tryakin, Matthew Goetz, Hope S Rugo, Elzbieta Senkus, Laura Testa, Michael Andersson, Kenji Tamura, Guenther G. Steger, Lucia Del Mastro, Joanne Cox, Tammy Forrester, Sarah Sherwood, Xuelin Li, Ran Wei, Miguel Martin, Priya Rastogi. Primary outcome analysis of invasive disease-free survival for monarchE: abemaciclib combined with adjuvant endocrine therapy for high risk early breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr GS1-01.