Three-year disease-free survival in randomized trials of neoadjuvant chemotherapy and HER2-targeted therapy in breast cancer: A meta-analysis

Neoadjuvant chemotherapy with either single or dual HER2-targeted therapy has emerged as the standard of care for many patients with HER2-positive (HER2+) breast cancer (Gradishar et al., 2020, Cardoso et al., 2019). With chemotherapy and dual HER2-targeted therapy (trastuzumab and pertuzumab), pathological complete response (pCR) is observed in up to 60% of patients (Gianni et al., 2012, Schneeweiss et al., 2018). Multiple meta-analyses have shown that patients who achieve a pCR have excellent long-term outcomes compared to those with residual disease at the time of surgery (Broglio et al., 2016, Spring et al., 2020, Cortazar et al., 2014).

The KATHERINE trial was a randomized, phase 3 trial in patients who had residual disease after neoadjuvant chemotherapy and HER2-targeted therapy and showed a significant improvement in 3-year disease-free survival (DFS) when trastuzumab was replaced by trastuzumab emtansine (T-DM1) in the postoperative setting (von Minckwitz et al., 2019). In this trial, patients with residual disease who continued on trastuzumab had a 3-year DFS of 77% while those switching to T-DM1 has a 3-year DFS of 88% translating to halving of the relative risk of recurrence and an absolute improvement in 3-year DFS of 11% with T-DM1.

HER2 + early breast cancer has variable outcome with a substantial component of heterogeneity associated with hormone receptor expression (Cejalvo et al., 2017, Prat et al., 2014a). Around 70% of HER-2 + are also hormone receptor positive (HR+) and may have lower relative response to chemotherapy and HER2-targeted therapy (Loibl et al., 2016, Carey et al., 2016, Dieci et al., 2016, Prat et al., 2014b). Moreover, recent studies suggest that some patients with residual disease after neoadjuvant chemotherapy and HER2-targeted therapy have very good outcomes, especially if HR+ . Steenbruggen et al (Steenbruggen et al., 2019). classified patients who did not achieve pCR based on residual cancer burden (RCB), Neoadjuvant Response Index (NRI) and Neo-Bioscore. Patients with pCR had 5-year recurrence-free interval (RFI) of 92%. Interestingly, patients with RCB 1, NRI 0.75–0.99 or a Neo-Bioscore between 0 and 1 had 5-year recurrence-free intervals within 3% of those with pCR (Steenbruggen et al., 2019). More recently, a pooled analysis of 1430 patients (756 of whom were HR+) with HER2 + disease also showed a nearly identical 3-year event-free survival (EFS) in HR+ and HER2 + patients who had RCB 1 disease compared to those with pCR (with both having >95% 3-year EFS). Those with RCB 1 and HR-negative (HR-) and HER2 + disease did only slightly worse with 3-year EFS close to 90% (Yau et al., 2022). Additionally, validation of the RCB score has shown that patients with stage I residual disease (ypT1N0) have excellent outcome with no significant difference between those classified as RCB class 1 and RCB class 2 (Symmans et al., 2017). Interestingly, the benefits of T-DM1 in these patients, especially if also HR+ have not been reported either in the primary publication or the subsequent subgroup analysis of KATHERINE trial (Mamounas et al., 2021). This raises the question of whether the benefit of adjuvant T-DM1 is meaningful in these good prognostic subgroups.

Assuming that T-DM1 in the post-operative setting provides a consistent halving of the risk of recurrence, the absolute benefit of this drug or any other adjuvant therapy (as well as the balance between benefit and risk) will depend on the expected outcomes in patients with residual disease continuing on trastuzumab. Therefore, an accurate estimate of 3-year DFS in this setting would be valuable for treatment planning. We performed a meta-analysis of randomized trials of neoadjuvant chemotherapy and HER2-targeted therapy exploring outcomes as well as factors associated with recurrence risk. We hypothesized that outcomes for patients who do not achieve a pCR are better than reported in older trials and consequently, the anticipated absolute benefit of T-DM1 in these patients is likely to be smaller.

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