No abstract

Based on the observation that b-HCG/LH-R was found to be selectively upregulated in invasive tumor components, we suggest that under certain circumstances, sensitivity of ductal cells to hormones that target b-HCG/LH-R could favour mammary carcinogenesis.

Background: Patients with HER2-positive early breast cancer who have residual invasive disease after neoadjuvant chemotherapy plus HER2-targeted therapy have a high risk of recurrence and death. The current standard of care is continuation of the same HER2-targeted therapy in the adjuvant setting for one year. T-DM1 has shown activity and a favorable benefit-risk profile in metastatic patients with disease progression after prior chemotherapy plus HER2-targeted therapy. Thus, T-DM1 may also be active in patients with residual invasive disease after neoadjuvant HER2-targeted therapy. 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 (IHC3+ or ISH+) primary breast cancer (T1–4, N0–3, M0) who received neoadjuvant chemotherapy plus 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 IV q3w) or trastuzumab (6 mg/kg IV q3w), for 14 cycles. Randomization was stratified by clinical stage at presentation, hormone receptor status, single versus dual neoadjuvant HER2-targeted therapy, and pathological nodal status after neoadjuvant therapy. Patients received radiotherapy and/or endocrine therapy per local standards. The primary endpoint is invasive disease-free survival (IDFS). A single interim analysis (IA) was planned after approximately 67% of the IDFS events required for the primary analysis had occurred, with an efficacy stopping boundary of HR?0.732 or p<0.0124. The statistical plan stipulated an IA of OS if the IDFS IA boundary was crossed. Secondary endpoints include IDFS including second primary non-breast cancer, disease-free survival, distant recurrence-free interval, overall survival, and safety. Results:After review of the pre-specified IA, the IDMC recommended full analysis and disclosure of the results. With 256 IDFS events reported, administration of T-DM1 significantly improved IDFS compared with trastuzumab (unstratified HR=0.50; 95% CI: 0.39 to 0.64; p<0.0001). IDFS events occurred in 91 patients (12.2%) in the T-DM1 arm compared with 165 patients (22.2%) in the trastuzumab arm. T-DM1 treatment increased estimated three-year IDFS rates (88.3% vs 77.0% with trastuzumab). A consistent benefit was shown across all stratification subgroups. With 98 deaths reported, the OS analysis is immature (HR=0.70; 95% CI: 0.47 to 1.05; p=0.085). The safety data were consistent with the known safety profile of T-DM1, with expected increases in AEs associated with T-DM1 compared to trastuzumab alone. One grade 5 AE (0.1%) occurred in each arm. Conclusions: Adjuvant T-DM1 substantially improved IDFS in patients with HER2-positive early breast cancer with residual disease after completion of neoadjuvant therapy. Citation Format: Geyer, Jr. CE, Huang C-S, Mano MS, Loibl S, Mamounas EP, Untch M, Wolmark N, Rastogi P, Fischer HH, Redondo A, Jackisch C, Jacot W, Conlin AK, Schneeweiss A, Wapnir IL, Fasching PA, DiGiovanna MP, Wuelfing P, Arce-Salinas C, Crown JP, Shao Z, Rota Caremoli E, Wu H, Lam LH, Tesarowski D, Smitt M, Douthwaite H, Singel SM, von Minckwitz G. Phase III study of trastuzumab emtansine (T-DM1) vs trastuzumab as adjuvant therapy in patients with HER2-positive early breast cancer with residual invasive disease after neoadjuvant chemotherapy and HER2-targeted therapy including trastuzumab: Primary results from KATHERINE [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 GS1-10.

515 Background: HR+/HER2+ breast cancer (BC) is a distinct entity associated with better prognosis compared to HR-/HER2+ BC. However, combination of chemotherapy (CT) with (dual) anti-HER2 blockade is standard in HER2+ early BC (EBC), irrespective of HR-status. Despite of some promising data on combination of endocrine therapy (ET) with dual anti-HER2 blockade in EBC and metastatic HR+/HER2+ BC, no prospective comparison of neoadjuvant CT vs. ET + dual HER2-blockade has yet been performed. Methods: In the prospective WSG TP-II phase II-trial (NCT03272477; Sponsor: Palleos GmbH, Wiesbaden, Germany), 207 patients (pts) (257 screened; 40 centers) with centrally confirmed HR+/HER2+ EBC were randomized to 12 weeks of standard ET (n=100) vs. paclitaxel 80 mg/m2 weekly (n=107) +trastuzumab+pertuzumab q3w for all pts. Primary endpoint was pCR (ypT0/is/ypN0). Secondary endpoints include safety, disease-free and overall survival, translational research, and quality of life (QoL). Omission of further CT was allowed in all pts with pCR; dual HER2-blockade was administered in the adjuvant setting in all pts. Results: Baseline characteristics were well balanced between the arms. Median age was 53 years; 58% had cT2-4, 28% had cN+; 43% had G3 tumors. pCR data were available in 198 pts (ET: n=96; Pac: n=102). pCR was observed in 24% (95% CI: 16-34%) with ET+T+P vs. 57% (95% CI:47-67%) with Pac+T+P (OR 0.24, 95% CI: 0-0.46, p<0.001). In multivariable logistic regression analysis and corresponding sensitivity analysis (bootstrap/subsample inclusion frequencies and lasso regression) including study arm, BMI, menopausal, cT, and cN status, histological grade, HER2-status, Ki67, ER, PR as continuous variables, only study arm and HER2 3+ status were significantly associated with pCR. Neoadjuvant treatment was well tolerated in both study arms and completed per protocol in 93/92 (ET+P+T/Pac+P+T) patients. Only 9/13 SAEs (ET+P+T/Pac+P+T) were reported during neoadjuvant therapy. PAM50 and QoL analysis are ongoing. Conclusions: WSG TP-II is the first randomized prospective trial comparing two neoadjuvant de-escalation treatments in HR+/HER2+ EBC. The excellent pCR rate of 57% after only 12 weeks of Pac+P+T was clearly superior to the still promising 24% pCR rate in pts treated by ET+P+T. In both arms, treatment efficacy was most pronounced in HER2 3+ tumors. Survival results need to be awaited before definite recommendations for a de-escalated regimen in HR+/HER2+ EBC can be made. Clinical trial information: 2016-005157-21 .