Editor's Note: Precision treatment for HER2-positive breast cancer has long been a focal point and challenge in breast cancer research. Recently, the DTP study (Abstract No.: RF1-07), presented at the 2024 San Antonio Breast Cancer Symposium (SABCS), offers new insights into addressing this challenge. This study aims to explore the efficacy and safety of combining durvalumab immunotherapy with dual-targeted therapy in the neoadjuvant treatment of early-stage HER2-positive breast cancer. The goal is to discover new diagnostic and therapeutic directions for HER2-enriched breast cancer driven by precision medicine. Oncology Frontier invited Professor Feng Jin fromThe First Affiliated Hospital of China Medical University and Dr. Xiaoman Jiang from The Second Hospital of Jilin University to provide an in-depth analysis and commentary on the DTP study.

Current Status of Neoadjuvant Treatment for High-Risk Early HER2-Positive Breast Cancer

At present, the neoadjuvant treatment for high-risk early-stage HER2-positive breast cancer primarily involves chemotherapy combined with anti-HER2 targeted therapy. Optimizing therapeutic regimens to improve pathological complete response (pCR) rates remains under active investigation. Clinical trials combining immunotherapy with anti-HER2 targeted therapy are also rapidly progressing. While immunotherapy has achieved notable success in the neoadjuvant treatment of triple-negative breast cancer (TNBC)—as demonstrated in the KEYNOTE-522 trial—ongoing trials such as KEYNOTE-756 and CheckMate 7FL have shown potential for neoadjuvant immunotherapy in HR+/HER2-negative early breast cancer. However, results of immunotherapy in HER2-positive breast cancer have been less promising, as seen in the IMpassion050 trial.

In this context, the DTP trial emerged as a promising approach, aiming to evaluate the efficacy and safety of a chemotherapy-free regimen combining durvalumab immunotherapy with dual-targeted therapy in the neoadjuvant setting for early-stage ER/PR-negative HER2-positive breast cancer. The study seeks to pioneer new treatment directions for HER2-enriched breast cancer within the framework of precision medicine.

Durvalumab is a human monoclonal antibody that binds to the PD-L1 protein, blocking its interaction with PD-1 and CD80 proteins. This action relieves PD-1/PD-L1-mediated immune suppression and promotes T-cell attack on tumor cells. In breast cancer research, durvalumab has been primarily studied in TNBC clinical trials. However, as early as 2016, durvalumab was already being explored for the treatment of HER2-positive breast cancer. The latest update from the DTP trial, compared to findings presented at the American Association for Cancer Research (AACR) in April 2024, includes PD-L1 combined positive score (CPS) correlation analysis. This update suggests that higher CPS scores in early-stage HER2-positive breast cancer patients may be associated with a greater likelihood of achieving pCR with this drug combination.

The DTP trial is a single-arm, prospective, open-label Phase II clinical study utilizing durvalumab. It enrolled 39 patients with previously untreated, stage I-III, ER/PR-negative, HER2-enriched breast cancer (based on BluePrint®, Agendia) from July 2020 to February 2024. Patients received durvalumab (1120 mg, every 3 weeks) combined with trastuzumab (8 mg/kg loading dose; 6 mg/kg every 3 weeks) and pertuzumab (840 mg loading dose; 420 mg every 3 weeks) for six cycles. The primary endpoint was the pathological response rate, defined as a Residual Cancer Burden (RCB) score of 0 or 1.

In the evaluable patient population, 67.6% achieved pathological response, with 48.6% reaching pathological complete response (pCR).

A subsequent multivariate analysis of pCR outcomes revealed a negative correlation with tumor size, lymph node metastasis status, and advanced staging, while a positive correlation was observed with tumor-infiltrating lymphocytes (TILs%) and PD-L1 combined positive score (CPS). Additionally, gene expressions related to luminal breast cancer, as identified by HER2DX testing, were also associated with pCR outcomes.

Moreover, HER2DX can predict pCR and long-term survival outcomes in HER2-positive early breast cancer (EBC) patients by analyzing the expression profile of 27 genes and clinical characteristics. Regarding safety, most adverse reactions in this trial were grade 1 or 2, indicating good tolerability.

Although prior studies have confirmed a potential synergistic effect between immune checkpoint inhibitors and anti-HER2 targeted therapies—such as trastuzumab inducing immune suppression by upregulating PD-L1 expression in macrophages—clinical trials so far have shown disappointing results for PD-1/PD-L1 inhibitors in HER2-positive metastatic breast cancer. Trials like PANACEA, KATE-2, JAVELIN Solid Tumors, and NCT02649686 did not achieve significant outcomes. However, PD-L1-positive groups in the PANACEA and KATE-2 studies showed a trend toward improved survival benefits.

In the NCT02649686 study, durvalumab did not exhibit significant antitumor activity, possibly due to the lack of PD-L1 expression in enrolled patients. It was also noted that early-stage breast cancer generally has stronger immune activity and lower tumor escape rates, favoring immune recognition and targeting of tumor antigens. Therefore, more refined patient selection could make immunotherapy a promising strategy for early-stage HER2-positive breast cancer. However, the IMpassion050 study, which evaluated the addition of PD-1/PD-L1 inhibitors to dual-targeted therapy and chemotherapy in neoadjuvant treatment, did not significantly improve pCR rates. In contrast, the Neo-PATH study showed that adding PD-1/PD-L1 inhibitors in ER-negative groups resulted in promising pCR rates and acceptable adverse effects.

Against this backdrop, the DTP trial introduced an innovative “de-escalation” treatment strategy in the neoadjuvant setting for HER2-enriched breast cancer by combining targeted therapy with immunotherapy, excluding chemotherapy. Building on previous research and clinical experience, the trial refined its participant criteria to ER/PR-negative patients and set the pathological response rate—defined as a Residual Cancer Burden (RCB) score of 0 or 1—as the primary endpoint. The DTP study achieved a notable 67.6% pathological response rate, comparable to standard chemotherapy regimens. Additionally, six patients with RCB >1 continued with standard chemotherapy, with 50% achieving pCR. Including these three patients, the overall pathological response rate increased to 75.7%, and the overall pCR rate rose to 56.8%.

Multivariate analysis again confirmed a positive correlation between TILs%, PD-L1 CPS, and pCR outcomes. HER2DX-identified luminal-type gene expressions were also linked to pCR outcomes. The study is continuing to explore tumor microenvironment interactions and immune cell dynamics through single-cell RNA sequencing and spatial transcriptomics conducted before and after treatment.

At this year’s SABCS, studies on neoadjuvant therapies for early HER2-positive breast cancer primarily focused on new drug combinations (e.g., margetuximab and SHR-A1811, an anti-HER2 antibody-drug conjugate) and more refined patient selection strategies using immunobiological characteristics, clinicopathological factors, and imaging analysis. The DTP study’s inclusion of durvalumab in its regimen presents an innovative, biomarker-driven, chemotherapy-free approach for treating HER2-enriched EBC patients. However, evidence supporting the use of immunotherapy combinations in HER2-positive breast cancer remains limited. Ongoing research is expected to provide more valuable data. With more precise patient selection based on molecular biomarkers and the exploration of multidimensional drug combinations, immunotherapy has significant future potential in the treatment of HER2-enriched breast cancer.

Reference

[1].Padmanabhan, R., et al., Crosstalk between HER2 and PD-1/PD-L1 in Breast Cancer: From Clinical  Applications to Mathematical Models. Cancers (Basel), 2020. 12(3).

[2].Chia, S., et al., A Phase Ib Trial of Durvalumab in Combination with Trastuzumab in HER2-Positive  Metastatic Breast Cancer (CCTG IND.229). Oncologist, 2019. 24(11): p. 1439-1445.

Professor Feng Jin

• Distinguished Professor, Chief Physician, and Doctoral Supervisor
• Department of Breast Surgery, First Affiliated Hospital of China Medical University
• Chair, Breast Cancer Professional Committee, Liaoning Anti-Cancer Association
• Chair, Breast Surgery Branch, Liaoning Medical Association
• Honorary Deputy Leader, Breast Cancer Group, Chinese Medical Association Oncology Branch
• Vice Chair, Breast Cancer Professional Committee, Chinese Anti-Cancer Association
• Executive Member, CSCO-BC, Chinese Society of Clinical Oncology
• Member, Breast Surgery Group, Surgery Branch, Chinese Medical Association
• Deputy Leader, Breast Surgery Expert Group, Surgery Branch, Chinese Medical Doctor Association
• Deputy Chair, Surgical Special Committee, Beijing Breast Disease Prevention and Treatment Society
• Head, Breast Surgery Group, Surgery Branch, Liaoning Medical Association

Dr. Xiaoman Jiang

• Physician, Department of Breast Surgery, Second Hospital of Jilin University
• Doctor of Oncology, China Medical University