Invasive Disease Free Survival and Brain Metastasis Rates in Patients Treated with Neoadjuvant Chemotherapy with Trastuzumab and Pertuzumab
Authors: Dang Chau , Chew Sonya , Ferraro Emanuela , Chen Yuan , Barrio Andrea , Kelly Daniel , Modi Shanu , Seidman Andrew , Wen Hannah , Brogi Edi , Robson Mark 
Published: October 2023

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 breast 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, 45 (17%) did not have HER2 retesting and were excluded from the final analysis. In the remaining 224 pts, 143 (64%) were HER2(+) and 81 (36%) were HER2(-). In the 143 pts with HER2(+) RD, adj T-DM1, HP, H alone and no HER2 directed therapy were received by 121 (85%), 16 (11%), 1 (1%) and 5 (3%) of pts, respectively. In the 81 pts with HER2(-) RD, adj T-DM1, HP, H alone and no HER2 directed therapy were received by 45 (56%), 27 (33%), 3 (4%) and 6 (7%) of pts, respectively. With a median follow up of 24 months, 8 patients developed BM at initial recurrence, 4/325 (1.2%) 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. Pts with RD 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 224 pts with RD, there was no difference in IDFS between 9/143 (6%) pts with HER2(+) RD or 5/81 (6%) 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 effective 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.