MammaPrint High 2 Indication Could Be Predictive Biomarker for Immunotherapy in HR+/HER2– Early Breast Cancer

Erin Frances Cobain, MD

In the prospective, observational FLEX trial (NCT03053193), patients with MammaPrint (MP) high 2 hormone receptor (HR)–positive, HER2-negative early-stage breast cancer exhibited a heightened immune active state—denoted by greater presence of immune cells and upregulation of antigen presentation genes—compared with MP high 1 tumors, indicating a predictive biomarker of immunotherapy benefit, according to data presented at the 2024 ASCO Annual Meeting.

Findings showed that patients with MP high 2 tumors (n = 624) had a higher abundance of antigen-presenting cells, including M1 macrophages and activated dendritic cells. Additionally, MP high 2 tumors were associated with a higher abundance of natural killer cells and a significantly lower abundance of neutrophils. Notably, within the MP high 2 subgroup, the MP high 2 basal subtype displayed increased innate immunity vs the luminal subtype.

Additionally, patients with MP high 2 tumors had a higher frequency of CD4-positive T and memory cells; CD8-positive T and Memory cells; B cells; memory B cells; and antibody-producing plasma cells compared with patients with MP high 1 tumors (n = 2292). Patients in the MP high 2 basal subgroup had greater adaptive immunity vs the MP high 2 luminal subtype.

"MP high 2 tumor status is a promising predictive biomarker of immunotherapy benefit in this population and merits further study as an integral biomarker to select patients for neoadjuvant chemoimmunotherapy treatment,” lead study author Erin Frances Cobain, MD, stated during the presentation.

Cobain is an assistant professor at the University of Michigan Health, Michigan Medicine, and a medical oncologist and co-director of the Breast Cancer Clinical Research Team at Rogel Cancer Center in Ann Arbor.

During the presentation, Cobain noted that despite neoadjuvant and adjuvant systemic therapies, patients with clinically and genomically high-risk HR-positive, HER2-negative early-stage breast cancer still face a risk of recurrence. Therefore, additional treatment options are necessary.

The addition of immune checkpoint inhibitors to neoadjuvant chemotherapy has been assessed in the phase 3 CheckMate-7FL (NCT04109066) and KEYNOTE-756 (NCT03725059) trials thus far, in which, patients with a high risk of recurrence were selected based on clinical stage, tumor grade, or estrogen receptor (ER) percentage. Both trials showed an improved likelihood of achieving a pathologic complete response (pCR) with chemoimmunotherapy compared with chemotherapy alone.

The 70-gene MammaPrint test is designed to classify patients with early-stage, HR-positive, HER2-negative breast cancer into high- and low-risk subgroups such as high 2, high 1, low, and ultralow. High 1 and 2 patients can benefit from adjuvant or neoadjuvant chemotherapy, and data suggest that individuals with MP high 2 tumors may have increased sensitivity to chemoimmunotherapy, PARP inhibition, and platinum-based chemotherapies.

Additionally, patients with MP high 2 HR-positive, HER2-negative early-stage breast cancer also benefited from neoadjuvant chemoimmunotherapy in the phase 2 I-SPY2 trial (NCT01042379), which the addition of an immune checkpoint inhibitor to chemotherapy elicited improved rates of pCR.

The use of chemoimmunotherapy for this patient population is being further investigated in the phase 3 SWOG S2206 trial (NCT06058377), which is enrolling patients with clinical stage II to III HR-positive, HER2-negative breast cancer, and the MammaPrint Test is being utilized as an integral biomarker. Patients with a MP high 2 score of –0.57 to –1 will be randomly assigned 1:1 to receive either standard-of-care neoadjuvant chemotherapy or standard chemotherapy in combination with durvalumab (Imfinzi; arm 2). Patients will then go on to receive standard surgery, radiation (if indicated), and endocrine (with or without targeted therapy). Follow-up will continue for 10 years.

In an analysis of patients enrolled in the observational FLEX trial, investigators sought to characterize the underlying biology that mediates the benefit of immunotherapy in patients with HR-positive, HER2-negative early-stage breast cancer classified as MP high 2. The study used gene expression and transcriptomic analyses to perform molecular classification via the MammaPrint assay to distinguish MP high 1 vs MP high 2; and the 80-gene BluePrint assay to identify luminal vs basal tumors.

Additionally, immune characterization was measured through the quantification of innate and adaptive immunity cell types using the gene signature method xCell; gene expression analyses of KEGG pathway genes; and PD-1 and PD-L1 expression via R package Limma.

Regarding the clinical characteristics of patients in FLEX, 79% of tumors were MP high 1 (n = 2292) and 21% were MP high 2 (n = 624). A higher proportion of patients with MP high 2 were 50 years of age or younger (31.9% vs 23.6%), and patients in the MP high 2 subgroup were more likely to have grade 3 tumors (71.6% vs 22.5%). MP high 2 tumors were more likely to have ER staining between 1% and 10% (16.8% vs 1.1%).

Additional data showed that upregulation of the MHC I and II pathways was observed at higher rates in patients with MP high 2 tumors, and this subgroup also had a significantly higher expression of PD-1 and PD-L1 compared with patients with MP high 1 tumors.

Reference

Cobain EF, Pusztai L, Graham CL, et al. Elucidating the immune active state of HR+HER2- MammaPrint High 2 early breast cancer. J Clin Oncol 2024;42(suppl 16):506. doi:10.1200/JCO.2024.42.16_suppl.506