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Background: Early biologic response to endocrine therapy, such as changes in Ki67 labeling index (LI), has been suggested to predict long-term outcomes in hormone sensitive breast cancer. The addition of a CDK4/6 inhibitor to endocrine therapy has been shown to augment biological response in breast cancer. Pre-operative Endocrine Prognostic Index (PEPI) scores, generated based on post-treatment Ki67 LI, have been shown to predict patient outcomes. EndoPredict® is a multigene assay that predicts the risk of distant recurrence in patients with operable estrogen receptor (ER)-positive HER2-negative breast cancer. This study was conducted to evaluate the efficacy of the neoadjuvant endocrine therapy plus palbociclib versus neoadjuvant endocrine therapy plus placebo. Patients and Methods: This is a phase III randomized, double-blind study of neoadjuvant hormonal therapy plus palbociclib versus neoadjuvant hormonal therapy plus placebo in untreated pre/peri- and post-menopausal women with operable, hormone receptor-positive (ER and/or progesterone receptor), HER2-negative breast cancer. The other major inclusion criteria included tumor size ≥ 15mm, T1c-3N0-1, Ki67 LI ≥14% by central assessment, and no previous history of radiotherapy or systemic therapy for breast cancer. Patients were randomly assigned 1:1 to receive 16 weeks of hormonal therapy plus palbociclib or hormonal therapy plus placebo. Hormonal therapy consisted of letrozole for post-menopausal patients and tamoxifen plus LH-RH agonist for pre/peri-menopausal patients. The co-primary endpoints included PEPI score and EPclin Risk Score, a score combining EndoPredict® molecular score with clinical factors. These scores were sequentially analyzed on a modified intent-to-treat basis according to the gatekeeping procedure: if statistical significance was detected on the PEPI score, the statistical significance of EPclin Risk Score would be assessed. The sample size was 100 patients in each arm, which was calculated with < 5% type I error rate (two sided) and 80% power. Results: Between 16 July 2019 – 7 July 2021, 141 eligible patients were randomized from 25 participating institutes in Japan, Korea, Taiwan, Hong Kong and Australia. One hundred twenty-six patients completed the treatment duration and surgical samples were collected to evaluate endpoints. All randomized patients were evaluable for safety assessment. Randomization was well-balanced in terms of age, menopausal status and cancer stage. The proportion of patients who had a low, moderate, or high PEPI score was 15.2%, 50.0% and 34.8% in the hormonal therapy plus palbociclib arm and 13.3%, 55.0% and 31.7% in the hormonal therapy plus placebo arm, respectively. There was no statistically significant difference in PEPI score between two arms (one-sided p-value=0.563). The proportion of patients who had a high risk EPclin Risk Score seemed lower in the palbociclib arm than in the placebo arm (62.1% vs 68.3%) although hypothesis testing was not performed on EPclin Risk Score because statistical significance was not detected on the PEPI score. No new safety signals were found in the study. Permanent discontinuation from the study in association with adverse events was reported for 7 (9.7%) patients in the hormonal therapy plus palbociclib arm and for 0 patients in the hormonal therapy plus placebo arm. Conclusions: The addition of palbociclib to neoadjuvant hormonal therapy did not improve efficacy measured by PEPI score. In palbociclib arm, the rate of patients who had a high risk EPclin Risk Score after treatment was lower than in placebo arm. Translational researches are ongoing to analyze molecular changes by treatments. The role of chemotherapy after neoadjuvant therapy is under investigation. Clinical trial identification: NCT03969121 Funding: Pfizer Inc. Citation Format: Takayuki Ueno, Louis W.C. Chow, Wonshik Han, Chiun Sheng Huang, G Bruce Mann, Satoshi Morita, Hironori Haga, Elham Fakhrejahani, Takayuki Kobayashi, Kenichi Inoue, Mariko Tokiwa, Hirofumi Suwa, Tomoyuki Aruga, Sachiko Minamiguchi, Yosuke Yamada, Yuko Tanabe, Masahiro Takada, Toshinari Yamashita, Hiroji Iwata, Chi-Feng Chung, Sachiko Takahara, Eriko Tokunaga, Shigeru Imoto, Eun Sook Lee, Yasuaki Sagara, Jee Hyun Kim, Richard H DeBoer, Hyun-Ah Kim, Hung Wen Lai, Ming-Feng Hou, Michelle White, Yoshiko Umeyama. Neoadjuvant hormonal therapy plus palbociclib versus hormonal therapy plus placebo in women with operable, hormone sensitive and HER2-negative primary 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 P5-09-01.

Trastuzumab emtansine is the current standard treatment for patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer whose disease progresses after treatment with a combination of anti-HER2 antibodies and a taxane.We conducted a phase 3, multicenter, open-label, randomized trial to compare the efficacy and safety of trastuzumab deruxtecan (a HER2 antibody-drug conjugate) with those of trastuzumab emtansine in patients with HER2-positive metastatic breast cancer previously treated with trastuzumab and a taxane. The primary end point was progression-free survival (as determined by blinded independent central review); secondary end points included overall survival, objective response, and safety.Among 524 randomly assigned patients, the percentage of those who were alive without disease progression at 12 months was 75.8% (95% confidence interval [CI], 69.8 to 80.7) with trastuzumab deruxtecan and 34.1% (95% CI, 27.7 to 40.5) with trastuzumab emtansine (hazard ratio for progression or death from any cause, 0.28; 95% CI, 0.22 to 0.37; P0.001). The percentage of patients who were alive at 12 months was 94.1% (95% CI, 90.3 to 96.4) with trastuzumab deruxtecan and 85.9% (95% CI, 80.9 to 89.7) with trastuzumab emtansine (hazard ratio for death, 0.55; 95% CI, 0.36 to 0.86; prespecified significance boundary not reached). An overall response (a complete or partial response) occurred in 79.7% (95% CI, 74.3 to 84.4) of the patients who received trastuzumab deruxtecan and in 34.2% (95% CI, 28.5 to 40.3) of those who received trastuzumab emtansine. The incidence of drug-related adverse events of any grade was 98.1% with trastuzumab deruxtecan and 86.6% with trastuzumab emtansine, and the incidence of drug-related adverse events of grade 3 or 4 was 45.1% and 39.8%, respectively. Adjudicated drug-related interstitial lung disease or pneumonitis occurred in 10.5% of the patients in the trastuzumab deruxtecan group and in 1.9% of those in the trastuzumab emtansine group; none of these events were of grade 4 or 5.Among patients with HER2-positive metastatic breast cancer previously treated with trastuzumab and a taxane, the risk of disease progression or death was lower among those who received trastuzumab deruxtecan than among those who received trastuzumab emtansine. Treatment with trastuzumab deruxtecan was associated with interstitial lung disease and pneumonitis. (Funded by Daiichi Sankyo and AstraZeneca; DESTINY-Breast03 ClinicalTrials.gov number, NCT03529110.).

Background The information of Oncotype DX applied in Asian breast cancer patients is limited. A recurrence index for distant recurrence (RI-DR) has been developed for early-stage breast cancer (EBC) from tumor samples in Chinese patients. In this study, we compared the prognostic performance of the Oncotype DX (ODx) recurrence score (RS) with the RI-DR for any recurrence risk type. Materials and methods One hundred thirty-eight (138) patients with hormone receptor-positive and human epidermal growth factor receptor 2-negative EBC who were previously tested with ODx were included for testing with the RI-DR. The cutoff score to partition the low- and high-risk patients was 26 for RS and 36 for RI-DR. The primary endpoint was recurrence-free survival (RFS). Results The concordance between the RI-DR and RS was 83% in N0 patients and 81% in node-positive patients when the RS score cutoff was set at 26. With a median follow-up interval of 36.8 months, the 4-year RFS for the high- and low-risk groups categorized by the RS were 61.9% and 95.0%, respectively (hazard ratio: 10.6, 95.0% confidence interval [CI]: 1.8–62.9). The 4-year RFS in the high- and low-risk groups categorized by the RI-DR were 72.6% and 98.5%, respectively (hazard ratio: 18.9, 95% CI: 1.8–138.8). Conclusion This paper illustrated the performance of RI-DR and ODx RS in breast cancer women in Taiwan. There was high concordance between the RI-DR and RS. The RI-DR is not inferior to the RS in predicting RFS in EBC patients. This study will fill the gap between the current and best practice in Chinese patients., Utilization of Oncotype DX is uncommon in Asia due to lack of clinical data. We compare a clinical-genomic model, developed from Taiwan, to Oncotype 21-gene panel in Chinese patients.

Purpose Breast-cancer-related lymphedema (BCRL) can be a transient or persistent condition. The aims of this study were to (1) identify and weigh the risk factors for persistent lymphedema (PLE) among all patients with BCRL and (2) establish a prediction model for the occurrence of PLE. Methods A cohort of 342 patients with BCRL with a median follow-up of 5 years after the onset of swelling was analyzed. PLE was defined as a hardening of the subcutaneous tissue, the persistence of the circumferential difference (CD) between arms, or a flare-up of swelling during follow-up. Multiple logistic regression was used to identify risk factors for PLE, including tumors, treatments, and patient-related factors. The prediction accuracy of the model was assessed using the area under the receiver operating characteristic curve (AUC). Results Of the 342 patients with BCRL, 229 (67%) had PLE. Multiple logistic regression analysis revealed that the number of lymph node metastases (p = 0.012), the maximal CD between arms at the first occurrence of swelling (p

Background: T-DXd is a HER2-targeting antibody-drug conjugate approved for the treatment of pts with advanced HER2+ mBC based on the DESTINY-Breast01 study (NCT03248492). DESTINY-Breast03 (NCT03529110) isa randomized, multicenter, open-label, phase 3 study assessing the efficacy and safety of T-DXd vs. T-DM1 in pts with HER2+ mBC previously treated with trastuzumab and taxane. In the primary analysis, T-DXd demonstrated a clinically meaningful and statistically significant improvement in PFS vs. T-DM1 (Corteset al, ESMO 2021). In this exploratory analysis, we provide additional efficacy and safety data in subgroups, including in pts with brain metastases (BMs). Methods: Pts were randomly assigned 1:1 to receive 5.4 mg/kg T-DXd or 3.6 mg/kg T-DM1 Q3W. Pts with clinically stable BMs were eligible. Lesions were measured per modified Response Evaluation Criteria in Solid Tumors version 1.1. The primary endpoint was progression-free survival (PFS) determined by blinded independent central review (BICR). PFS and overall response rate (ORR) were analyzed for subgroups.Sites of progression and post-end-of-study therapies were also investigated. Results: At data cutoff (May 21, 2021), 524 pts were randomly assigned to T-DXd (n=261) orT-DM1 (n=263). T-DXd demonstrated superior PFS by BICR vs. T-DM1 (HR, 0.28 [95%CI, 0.22-0.37]; P=7.8 x 10-22); median (m) PFS by BICR was not reached (95% CI, 18.5-NE) for T-DXd compared with 6.8 mo (95% CI, 5.6-8.2) forT-DM1. For pts with stable BMs at baseline (n=82), mPFS was 15.0 mo (95% CI,12.5-22.2) for T-DXd vs. 3.0 mo (95% CI, 2.8-5.8) for T-DM1 (HR, 0.25 [95% CI,0.31-0.45)]. Overall, confirmed ORR for T-DXd was 79.7% vs. 34.2% for T-DM1.For patients with stable BMs at baseline, ORR was 67.4% for T-DXd vs. 20.5% forT-DM1. Consistent PFS and ORR benefit was also observed across other subgroups(Table 1). At data cutoff, 84 (32.2%) pts treated with T-DXd had progressive disease (PD) versus 155 (58.9%) with T-DM1. In pts with stable BMs in the T-DXd arm, 48.8% of pts (21/43) had PD. In pts with stable BMs in the T-DM1 arm, 69.2%of pts (27/39) had PD. Data on sites of progression will be presented. Further analyses are underway and will be presented. Overall, the safety profile of T-DXd was manageable and comparable with its known safety profile. Adjudicated drug-related interstitial lung disease/pneumonitis was reported in 27 (10.5%) pts treated with T-DXd and 5 (1.9%) pts treated with T-DM1 overall, with no grade 4 or 5 events. Additional new safety data will be presented. Conclusion: DESTINY-Breast03,the first-reported randomized phase 3 trial comparing T-DXd to standard of care, met the primary endpoint with T-DXd demonstrating superior PFS vs. T-DM1and T-DXd had a manageable safety profile. In this exploratory analysis, consistent PFS and ORR benefit with T-DXd vs. T-DM1 was observed across subgroups in pts with HER2+ mBC previously treated with trastuzumab and taxane, including in pts with BMs. Table 1.Subgroup Analyses forPFS and ORR of T-DXd versus T-DM1PFS by BICR HR (95% CI)Absolute ORR Difference (T-DXd-T-DM1) (95% CI)All patients (N=524)0.28 (0.22-0.37)45.5 (37.6-53.4)Hormone receptorPositive (n=272)0.32 (0.22-0.46)47.3 (36.1-58.4)Negative (n=248)0.30 (0.20-0.44)43.2 (31.5-55.0)Prior pertuzumabYes (n=320)0.31 (0.22-0.43)46.7 (36.5-56.9)No (n=204)0.30 (0.19-0.47)43.6 (30.5-56.7)Prior lines of therapya0-1 (n=258)0.33 (0.23-0.48)39.3 (27.3-51.2)≥2 (n=266)0.28 (0.19-0.41)51.6 (40.9-62.4)Visceral disease Yes (n=384)0.28 (0.21-0.38)48.3 (39.1-57.6)No (n=140)0.32 (0.17-0.58)39.1 (23.6-54.6)Brain metastases at baseline Yes (n=82)0.25 (0.13-0.45)46.9 (25.6-68.3)No (n=442)0.30 (0.22-0.40)45.5 (36.9-54.1) Citation Format: Sara Hurvitz, Sung-Bae Kim, Wei-Pang Chung, Seock-Ah Im, Yeon Hee Park, Roberto Hegg, Min-Hwan Kim, Ling-Ming Tseng, Vanessa Petry, Chi-Feng Chung, Hiroji Iwata, Erika Hamilton, Giuseppe Curigliano, Binghe Xu, Caleb Lee, Yali Liu, Jillian Cathcart, Emarjola Bako, Sunil Verma, Javier Cortés. Trastuzumab deruxtecan (T-DXd; DS-8201a) vs. trastuzumab emtansine (T-DM1) in patients (pts) with HER2+ metastatic breast cancer (mBC): subgroup analyses from the randomized phase 3 study DESTINY-Breast03 [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 GS3-01.

1061 Research Funding: Odonate Therapeutics, Inc. Background: T is a novel, oral taxane with unique properties, including: oral administration with a low pill burden, a long (8-day) half-life in humans, once-every-3-weeks dosing, no observed hypersensitivity reactions and significant activity against chemotherapy (CT)-resistant breast cancer cell lines. T had encouraging monotherapy activity in a phase 2 study in 38 pts with HR+, HER2- MBC, with a confirmed objective response rate (ORR) per RECIST 1.1 of 45% (Seidman, 2018 ASCO Annual Meeting, Abstract 1042). In CONTESSA, a randomized phase 3 study in 685 pts with HR+, HER2- MBC previously treated with a taxane, T plus a reduced dose of C improved progression-free survival (PFS) as assessed by the Independent Radiologic Review Committee (IRC) vs. the approved dose of C alone: median of 9.8 months (mo) vs. 6.9 mo, an improvement of 2.9 mo (HR=0.716; p=0.003) (O'Shaughnessy, SABCS 2020, GS4-01). Methods: CONTESSA 2 is a multinational, multicenter, phase 2 study of T (27 mg/m2 on day 1 of a 21-day cycle) plus a reduced dose of C (1,650 mg/m2/day for 14 days of a 21-day cycle) in pts with HR+, HER2- MBC previously treated with 0-1 prior CT regimens for MBC and not previously treated with a taxane. The primary endpoint is ORR as assessed by the IRC. The secondary efficacy endpoints are duration of response (DoR), PFS and disease control rate (DCR) as assessed by the IRC, and overall survival (OS). Results: 150 pts were enrolled and treated. 80% had visceral disease, 46% had de novo MBC, 52% were previously treated with a CDK 4/6 inhibitor and 33% were ≥65 years old. At the prespecified interim analysis approx 4 mo after the last patient enrolled, the confirmed ORR was 51% (95% CI: 42%-60%), and the unconfirmed ORR was 63% (95% CI: 54%-71%). The median DoR was 9.5 mo (95% CI: 5.4-11.5 mo), the median PFS was 12.9 mo (95% CI: 8.1 mo-NR) and the DCR was 71% (95% CI: 62%-79%). OS data are immature. Grade (Gr) ≥3 treatment-emergent adverse events (TEAEs) occurring in ≥5% of pts were: neutropenia (74.0%), leukopenia (10.7%), hypokalemia (7.3%), anemia (6.7%), hand-foot syndrome (6.0%) and diarrhea (5.3%). Gr 2 alopecia occurred in 11.3% of pts, febrile neutropenia occurred in 4.7% of pts and Gr ≥3 neuropathy occurred in 2.0% of pts. Discontinuation of T and C due to any adverse event occurred in 13.3% of pts. Conclusions: An all-oral regimen of T plus a reduced dose of C demonstrated a high level of antitumor activity in pts with HR+, HER2- MBC not previously treated with a taxane. The confirmed ORR was 51%, median DoR was 9.5 mo and median PFS was 12.9 mo. Neutropenia was the most frequent Gr ≥3 TEAE; the rate of febrile neutropenia was 4.7%. Rates of clinically significant alopecia and neuropathy were low. Clinical trial information: NCT03858972 . Clinical trial information: NCT03858972 .