SAKK – YOUNG ONCOLOGY ACADEMY

Update – Novelties in neoadjuvant therapy of breast cancer

Neoadjuvant chemotherapy (NACT) has become a mainstay of treatment for patients with triple-negative breast cancer (TNBC), and human epidermal growth factor 2 (HER2) positive BC. In these patients pathological complete response (pCR) is correlated with long term outcome and allows to adapt adjuvant treatment. Some patients with hormone receptor (HR) positive HER2-negative BC also require NACT, mainly because of locoregionally advanced disease or aggressive biology.
Neoadjuvant pembrolizumab in TNBC: 5-year event-free survival in Keynote-522 The Keynote-522 study randomized 1’174 patients with higher risk TNBC (cT1c cN1-2 or cT2-4 cN0-2) to either neoadjuvant chemotherapy (NACT) with pembrolizumab followed by adjuvant pembrolizumab (n = 784) or NACT with placebo (n = 390). The event-free survival (EFS) at 60-months was 81.3 % (95 %CI 78.4-83.9) in the pembrolizumab arm, and 72.3 % (95 % CI: 67.5–76.5) in the placebo arm, representing a significant (HR: 0.63; 95 % CI: 0.49–0.81) and sustained difference compared to the last interim-analysis after 36-months (HR 0.63; 95 % CI: 0.48–0.82). The benefit was irrespective of PD-L1 status and a difference between the two arms seems to emerge even in the patients having reached pCR (HR: 0.65; 95 % CI:0.39–1.08). Overall survival results were not presented (1).

a pCR and breast surgery was subsequently omitted, with all patients undergoing adjuvant whole breast radiotherapy and tumor bed boost. At a median follow-up of 38.4 months zero events were registered, resulting in an in-breast recurrence-free survival of 100 %.
Conclusions In TNBC, EFS results were confirmed. Next, overall survival results are eagerly awaited. Other studies may potentially open completely new treatment paths for high-risk ER+/HER2- BC. It will be incremental to see, whether the presented increased pCR rates translate to improved survival also in this cohort. And finally, further deescalation of surgical treatment after NACT was shown to harbor excellent oncologic results in a small cohort after 3-years of follow-up being highly relevant for the Swiss-initiated SAKK 23/18 VISION-1 trial (clinicaltrials.gov NCT04289935).
Author: Martin Heidinger, Breast center, University Hospital Basel, Switzerland, Tumor heterogeneity, metastasis, and resistance lab, Department of Biomedicine, University Hospital, Basel, Switzerland and University of Basel, Switzerland Mentor: PD Dr. Khalil Zaman, Breast center, Department of Oncology, Lausanne University Hospital CHUV, Lausanne, Switzerland

Neoadjuvant immunotherapy in HR positive and HER2 negative breast cancer The rationale to use PD-1/PD-L1 inhibitors in patients with HR+/HER2- BC stems from the I-Spy2 study suggesting improved pCR rates with these agents (2–5). Two studies investigating immune checkpoint inhibitors in these patients were presented at ESMO 2023. In the Keynote-756 study 1’278 patients with grade 3, ER ≥1 % and cT1c-2 cN1-2 or cT3-4 cN0-2 BC were randomized 1:1 (6). In the CheckMate 7FL study 510 patients with grade 3 and ER ≥1 % or grade 2 and ER 1-10 % BC and a tumor stage of cT1c-T2 cN1-2 or cT3-4 cN0-2 were randomized 1:1 (7). The patients received neoadjuvant pembrolizumab/placebo or nivolumab/placebo with NACT and post-surgical pembrolizumab/placebo or nivolumab/placebo with endocrine therapy, respectively. Both studies reported significantly improved pCR rates (Keynote-756: 24.3 % vs. 15.6 %; CheckMate 7FL: 24.5 % vs. 13.8 %). Discontinuation rates were higher in the immunotherapy arms compared to placebo (Keynote-756: 19.1 % vs. 10.1 %; CheckMate7FL: 10 % vs. 3 %). One treatment-related death occurred in the pembrolizumab arm and two deaths in the nivolumab arm. In the CheckMate 7FL cohort, no higher proportion of breast-conserving surgery was observed (38 % vs. 39 %).
Omission of breast surgery in breast cancer patients with excellent response to neoadjuvant chemotherapy Three-year follow-up data of a phase-2 multicenter prospective trial examining the omission of breast surgery after NACT in TNBC and HER2+ BC were presented. Patients had to have radiological complete or partial response and confirmed pCR on image-guided biopsy (8). Of 50 enrolled patients with cT1-2 cN0-1, 31 (62 %) showed

Acknowledgements: I would like to thank the SAKK for giving me the opportunity to participate in the Young Oncology Academy, the SAKK staff for the organization, and especially PD Dr. Khalil Zaman for providing mentorship, introducing me to the SAKK Breast group and providing guidance in the preparation of this ESMO update.
References 1. Foulkes WD et al.: Triple-Negative Breast Cancer. N Engl J Med. 2010;363:1938–1948. 2. Nanda R et al.: Pembrolizumab plus standard neoadjuvant therapy for high-risk breast cancer (BC):
Results from I-SPY 2. J Clin Oncol. 2017;35:506. 3. Nanda R et al.: Effect of Pembrolizumab Plus Neoadjuvant Chemotherapy on Pathologic Complete Res-
ponse in Women With Early-Stage Breast Cancer: An Analysis of the Ongoing Phase 2 Adaptively Randomized I-SPY2 Trial. JAMA Oncol. 2020;6:676–684. 4. Wolf DM et al.: Redefining breast cancer subtypes to guide treatment prioritization and maximize response: Predictive biomarkers across 10 cancer therapies. Cancer Cell. 2022;40:609-623.e6. 5. Huppert LA et al.: Pathologic complete response (pCR) rates for HR+/HER2- breast cancer by molecular subtype in the I-SPY2 Trial. J Clin Oncol. 2022;40:504. 6. Cardoso F et al.: KEYNOTE-756: A randomized, double-blind, phase III study of pembrolizumab or placebo with neoadjuvant chemotherapy and adjuvant endocrine therapy for high-risk, early-stage, ER+/ HER2 - breast cancer. Ann Oncol. 2019;30:ix7–ix8. 7. Loi S et al.: A phase III trial of nivolumab with neoadjuvant chemotherapy and adjuvant endocrine therapy in ER+/HER2- primary breast cancer: CheckMate 7FL. J Clin Oncol. 2020;38:TPS604–TPS604. 8. Kuerer HM et al.: Eliminating breast surgery for invasive breast cancer in exceptional responders to neoadjuvant systemic therapy: a multicentre, single-arm, phase 2 trial. Lancet Oncol. 2022;23:1517– 1524.

18 SCHWEIZER ZEITSCHRIFT FÜR ONKOLOGIE 1/2024