Abstract ES1-1: Escalating and de-escalation - titrating the right regimen in early stage HER2 positive
Journal: Cancer Research (2022)

Abstract In HER2+ early breast cancer (EBC), treatment concepts so far do not differ according to hormone receptor (HR) status except for adding adjuvant endocrine therapy (ET) in HR+. Nevertheless, preclinical research shows that molecular subtype distributions differ between HR+ and HR- HER2+ with HER2-enriched subtype being more frequent in HR-. In the context of anti-HER2 therapy the clinical impact of biomarkers such as PIK3CA mutations also differs between HR+ and HR-. Moreover, in the neoadjuvant setting, pCR rates differ between HR+ and HR- HER2+ EBC with lower rates in HR+. Yet, the prognostic impact of pCR on outcome in HR+ HER2+ is less pronounced than in HR- HER2+ tumors. Standard therapy for small tumors (pT1 pN0) includes primary surgery followed by adjuvant weekly paclitaxel and 1y trastuzumab, independent of HR status. In all larger node-negative and in node-positive tumors, neoadjuvant chemotherapy with dual HER2 blockade is recommend. Adjuvant therapy is then individualized based on pCR status with antibody therapy continued for 1y in case of pCR and 14 cycles of T-DM1 in case of non-pCR. Based on the ExteNET trial, 1y neratinib is approved as an extended adjuvant anti-HER2 therapy. In Europe, the approval is restricted to high-risk HR+ HER2+ EBC within 1y after trastuzumab therapy based on ExteNET subgroup analyses. Escalation of the endocrine component in high-risk HR+ HER2+ EBC is currently evaluated in eMonarcHER2 by adding abemaciclib to T-DM1 and ET after non-PCR. Regarding de-escalation, TBCRC0023, one of the first chemotherapy-free de-escalation studies in HER2+ EBC, looked at duration of neoadjuvant trastuzumab and lapatinib - in HR+ tumors together with letrozole (+ GNRH if premenopausal). Longer therapy duration led to higher in-breast pCR rates, particularly in the ER+ subgroup (33% after 24 vs. 9% after 12 weeks). WSG ADAPT was the first subtype-specific umbrella trial aiming at tumor-biology adapted therapy de-escalation in EBC; all neoadjuvant sub-trials evaluated 12 weeks of preoperative therapy and allowed patients with a pCR to omit further standard chemotherapy. For HR+/HER2+, there are two neoadjuvant trials, ADAPT TP (triple-positive) and TP II, so far. In ADAPT TP, 4x T-DM1 led to a total pCR (breast and nodes) of 41% - independent of concomitant ET, whereas trastuzumab + ET only rendered 15%. pCR was prognostic for outcome; in patients with pCR, further standard chemotherapy did not improve survival. In TP II, 12x weekly paclitaxel + trastuzumab + pertuzumab achieved a total pCR rate of 57%, whereas the antibodies alone + ET rendered 24%. Individualizing therapy by escalation or de-escalation holds great promise in HER2+ EBC, but the full potential of taking HR-status into account for such strategies has not yet been explored. We now know that a pCR achieved with a de-escalated regimen is clinically meaningful and that de-escalation trials are safe for participating patients in HR+ HER2+ EBC - provided patients and physicians have the option for therapy escalation if clinically needed. The neoadjuvant strategy offers an ideal setting for de-escalation and escalation concepts based on pCR status as well as on early response assessment by biomarkers and conventional or molecular imaging. Optimal endpoints in HR+ HER2+ disease differ according to molecular subtype. As demonstrated in ADAPT TP, HER2-enriched subtype is associated with high pCR rates after HER-targeting regimens whereas luminal A and B subtypes have lower pCR rates. In luminal tumors, survival endpoints may thus be more appropriate to fully evaluate de-escalated regimens.In clinical routine, individualized therapy concepts including therapy de-escalation and escalation should always be evidence-based in order not to jeopardize the already excellent survival rates we have achieved over the last decade in HR+ HER2+ EBC. Citation Format: Escalating and de-escalation - titrating the right regimen in early stage HER2 positive [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr ES1-1.