The human epidermal growth factor receptor 2 (HER2) tyrosine kinase receptor is overexpressed in approximately 20-30% of human breast cancers, and is associated with reduced survival. Hence, numerous therapeutic strategies have been tested for their ability to target the HER2 protein. The humanized monoclonal antibody trastuzumab (Herceptin) was the first HER2-targeted agent approved for clinical use in breast cancer patients. Response rates to single-agent trastuzumab range from 12 to 34% for metastatic breast cancer (MBC), and significant improvements in survival rates are achieved in patients with earlystage HER2-overexpressing breast cancer in the adjuvant setting. Despite its initial efficacy, acquired resistance to trastuzumab develops in a majority of patients with MBC, and a large subset never responds, demonstrating primary resistance. Molecular mechanisms of trastuzumab antineoplastic activity and potential mechanisms contributing to its resistance will be discussed in this review. Novel agents that may enhance trastuzumab efficacy will also be discussed.
Prolonged treatment with the potent bisphosphonates pamidronate and zoledronic acid seems to be well tolerated and should be studied in prospective, randomized studies to document prolonged skeletal efficacy.
#6077 Background
 The purpose of this study was to determine the incidence of brain metastases in a cohort of women with early stage triple-receptor negative breast cancer and to evaluate the survival outcomes of these patients.
 Method
 Six hundred and seventy nine patients with early stage triple-receptor negative breast cancer diagnosed between 1980 and 2006 were identified. Cumulative incidence of brain metastases at 2- and 5-years following a diagnosis of early-stage triple receptor-negative breast cancer considering death as a competing risk was computed. Time to brain metastases was computed from the date of breast cancer diagnosis to the date of development of brain metastases. Cox proportional hazards models, adjusted for various patient and tumor characteristics, were then fitted to explore factors that could predict for the subsequent development of brain metastases in this cohort. Survival following a diagnosis of brain metastases was measured from the date of brain metastases diagnosis to the date of death from any cause. All survival outcomes were computed using the Kaplan – Meier product limit method and compared across groups using log rank statistic.
 Results
 Median age was 50 years (range 22 to 97 years) and median follow-up was 26.9 months (range 1.1 to 321.3 months. Overall 42 (6.2%) patients developed brain metastases of whom 16 (38.1%) had 3 brain lesions or less, 19 (45.2%) had more than 3 brain lesions and number of brain lesions was unknown in 7 (16.7%) patients. Overall cumulative incidence at 2- and 5-years was 5.6% (95% CI 3.8%-7.9%) and 9.6% (95% CI 6.8% - 13%) respectively. Twenty –four (3.5%) patients developed brain metastases as the first site of recurrence with cumulative incidence at 2- and 5-years observed to be 2.0% (95% CI 2.6% -6.0%) and 4.9% (95% CI 3.2%-7.0%) respectively. In the multivariable model factors such as age at primary tumor diagnosis, initial clinical stage, histological tumor grade, number of lymph nodes examined and tumor lymph-vascular invasion were not significantly associated with time to brain metastases. For the whole group of patients who developed brain metastases median survival was 2.9 months (95% CI 2.0 – 7.6 months). Among those who developed brain metastases as the first site of recurrence median survival was 5.8 months (95% CI 1.7 – 11.0 months).
 Conclusion
 Data from published studies have reported a 5-year cumulative incidence of brain metastases of approximately 5 % in an unselected breast cancer population. In our large single institutional study patients with triple-receptor-negative breast tumors we report higher early cumulative incidence compared to historical controls associated with poor survival. Patients with triple-receptor negative breast tumors may be an ideal cohort to target brain metastases preventive strategies. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6077.
Background T-DM1 has improved PFS and OS in HER2+ advanced BC patients (pts) who previously progressed on trastuzumab and a taxane (Verma NEJM 2012). Preclinical data show that atezo (anti–PD-L1) inhibits PD-L1 binding to PD-1 and B7.1 to restore antitumor immunity. PD-L1 is often expressed on tumor-infiltrating immune cells (IC) in BC. KATE2 (NCT02924883) is the first study to assess atezo combined with T-DM1 in previously treated HER2+ advanced BC. Method Eligible pts had HER2+ advanced BC previously treated with trastuzumab and a taxane and progressed on treatment for metastatic disease or within 6 mo of adjuvant therapy. Pts were randomized 2:1 to atezo 1200 mg or pbo+T-DM1 3.6 mg/kg IV q3w (crossover not permitted). The primary endpoint was investigator-assessed PFS per RECIST v1.1. Additional endpoints included OS, ORR, DoR (secondary), PFS in the PD-L1+ subgroup (exploratory) and safety. Data cutoff: 11 Dec 2017. Result 133 pts were randomized to atezo+T-DM1 and 69 pts to pbo+T-DM1. 49% and 46% received prior pertuzumab for metastatic BC; median duration of pertuzumab treatment was 10 and 13 mo, respectively. Median follow-up was 8.5 and 8.4 mo, respectively. Efficacy in the ITT population and biomarker subgroups are shown. PFS HR was 0.82 (95% CI: 0.55, 1.23); p=0.3332. At data cutoff, 13 OS events (10%) in the atezo+T-DM1 arm and 8 (12%) in the pbo+T-DM1 arm had occurred. mDoR was not reached. 44% and 41% of safety-evaluable pts had an AE of Gr ≥3 with atezo+T-DM1 and pbo+T-DM1, respectively. The most common was thrombocytopenia (13% and 4%). The incidence of serious AEs (SAEs) was 33% with atezo+T-DM1 and 19% with pbo+T-DM1, with the most common being Gr 1-2 pyrexia with atezo+T-DM1 (5%) and abdominal pain (3%) and seizure (3%) with pbo+T-DM1. AE rates leading to atezo/pbo or T-DM1 discontinuation were 25% and 15%, respectively, with atezo+T-DM1 and 15% and 13% with pbo+T-DM1. 1 patient in the atezo+T-DM1 arm had a drug-related Gr 5 AE (hemophagocytic syndrome). ITT and Biomarker Subgroups: Efficacy Atezo+T-DM1 (n=133)Pbo+T-DM1 (n=69)mPFS, mo8.26.86-mo PFS, %585112-mo PFS, %3834ORR, %a4543CR67PR3936PD-L1 IHCb PD-L1+PD-L1-PD-L1+PD-L1-Patients, n57762742mPFS, mo8.56.84.18.2ORR, %a54403350Stromal TILsc TIL-high (≥5%)TIL-low (<5%)TIL-high (≥5%)TIL-low (<5%)Patients, n80454025mPFS, mo8.55.55.3NAORR, %a48383848HER2c IHC3+IHC0-2+IHC3+IHC0-2+Patients, n103305613mPFS, mo8.55.98.04.0ORR, %a52234631aORR-evaluable pts (measurable disease at baseline): n=132 in atezo+T-DM1 arm. bPD-L1+, IC1/2/3; PD-L1–, IC0; measured per the VENTANA SP142 IHC assay. cPost hoc exploratory analyses. Conclusion Atezo+T-DM1 did not demonstrate a clinically significant PFS benefit vs pbo+T-DM1; OS and DoR data are not yet mature. Numerically higher PFS and ORR were seen with atezo+T-DM1 in PD-L1+ pts. T-DM1 safety in both arms was consistent with its known profile. Although the combination of atezo+T-DM1 showed a numerically higher incidence of SAEs and discontinuation of atezo due to an AE, rates of Gr 3-5 AEs were similar between arms. Additional biomarker data, including gene expression and mutation data, will be presented. Citation Format: Emens LA, Esteva F, Beresford M, Saura C, De Laurentiis M, Kim S-B, Im S-A, Patre M, Wang Y, Mani A, Liu H, de Haas S, Loi S. Results from KATE2, a randomized phase 2 study of atezolizumab (atezo)+trastuzumab emtansine (T-DM1) vs placebo (pbo)+T-DM1 in previously treated HER2+ advanced breast cancer (BC) [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr PD3-01.
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