Invasive disease free survival and brain metastasis rates in patients treated with neoadjuvant chemotherapy with trastuzumab and pertuzumab.
Authors: Chew Sonya , Ferraro Emanuela , Chen Yuan , Barrio Andrea Veronica , Kelly Daniel W. , Modi Shanu , Seidman Andrew David , Wen Hannah Yong , Brogi Edi , Robson Mark E. , Dang Chau T. 
Published: June 2023

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Background: Patients (pts) with human epidermal growth factor receptor 2 (HER2) positive (+) early breast cancer (EBC) receiving neoadjuvant systemic therapy (NAST) have poorer outcomes if they have residual disease (RD) after surgery. HER2 negative (-) RD has been reported in 1/3 of pts after NAST. The KATHERINE trial suggests that pts with HER2- RD (8%) have better invasive disease-free survival (IDFS) with adjuvant (adj) trastuzumab emtansine (T-DM1) versus trastuzumab (H) alone. However, only 18% of the pts enrolled in the trial received NAST with trastuzumab and pertuzumab (HP). We aimed to analyze IDFS and brain metastasis (BM) rates in pts with HER2+ EBC in a modern population homogenously treated with NAST. We also report the incidence of pts with HER2- RD and their outcomes. Methods: Clinicopathologic data for pts with HER2+ EBC who received NAST between 1 Jan 2019 and 31 Jan 2022 were reviewed. External assessment of HER2 status before NAST was allowed. HER2 status of the surgical specimens with RD were assessed internally at our center. IDFS was defined as the time from surgery until first occurrence of invasive cancer recurrence, distant recurrence, or death from any cause. Results: The total cohort was 594 pts. 456 (77%) and 138 (23%) received antracycline-taxane and taxane based chemotherapy, respectively during NAST. 587 (99%) received HP and 7 (1%) received H alone. NAST was completed by 566 (95%) of pts. pCR (ypT0/isN0) was achieved in 325 (55%) and RD was seen in 269 (45%) pts. In 269 pts with RD, 46 (17%) did not have HER2 retesting and were excluded from the final analysis. In the remaining 223 pts, 143 (64%) were HER2+ and 80 (36%) were HER2-. In the 143 pts with HER2+ RD, adj TDM1, HP, H alone and no HER2 directed therapy were received by 120 (84%), 16 (11%), 1 (1%) and 6 (4%) of pts, respectively. In the 80 pts with HER2- RD, adj TDM1, HP, H alone and no HER2 directed therapy were received by 44 (55%), 27 (34%), 3 (4%) and 6 (7%) of pts, respectively. With a median follow up of 24 months, 7 pts developed BM at initial recurrence, 3/325 (0.9%) with pCR and 4/143 (2.8%) with HER2+ RD. None of the pts who developed BM had HER2- RD. IDFS events occurred in 22/594 (3%) pts. RD pts had a higher likelihood of having an IDFS event, 14/269 (5%) in RD and 8/325 (2%) in pCR (p = 0.04). In the evaluable 223 pts with RD there was no difference in IDFS between 10/143 (7%) pts with HER2+ RD or 4/80 (5%) with HER2- RD (p = 0.10). Conclusions: At a single center, in pts who predominantly received HP with chemotherapy as NAST, pts with RD had higher IDFS events than those with pCR. In those with RD, 36% lost HER2+ status; IDFS events appeared similar in those with HER2+ RD versus those with HER2- RD. The HER2 loss rate is higher than reported in KATHERINE possibly due to majority of pts receiving dual HP as NAST. The BM events seen in those with RD and pCR highlights the need for more effective therapy in NAST and adj setting to minimize BM risk.