Refining patient selection for breast cancer immunotherapy: beyond PD-L1

Abstract

Therapies that modulate immune response to cancer, such as immune checkpoint inhibitors, began an intense development a few years ago; however, in breast cancer (BC), the results have been relatively disappointing so far. Finding biomarkers for better selection of BC patients for various immunotherapies remains a significant unmet medical need. At present, only tumour tissue programmed death-ligand 1 (PD-L1) and mismatch repair deficiency status are approved as theranostic biomarkers for programmed cell death-1 (PD-1)/PD-L1 inhibitors in BC. However, due to the complexity of tumour microenvironment (TME) and cancer response to immunomodulators, none of them is a perfect selector. Therefore, an intense quest is ongoing for complementary tumour-or host-related predictive biomarkers in breast immuno-oncology. Among the upcoming biomarkers, quantity, immunophenotype and spatial distribution of tumour-infiltrating lymphocytes and other TME cells as well as immune gene signatures emerge as most promising and are being increasingly tested in clinical trials. Biomarkers or strategies allowing dynamic assessment of BC response to immunotherapy, such as circulating/exosomal PD-L1, quantity of white/ immune blood cell subpopulations and molecular imaging are particularly suitable for immunotreatment monitoring. Finally, host-related factors, such as microbiome and lifestyle, should also be taken into account when planning integration of immunomodulating therapies into BC management. As none of the biomarkers taken separately is accurate enough, the solution could come from composite biomarkers, which would combine clinical, molecular and immunological features of the disease, possibly powered by artificial intelligence.

The Transcriptomic Portrait of Locally Advanced Breast Cancer and Its Prognostic Value in a Multi-Country Cohort of Latin American Patients

“…CYT was also proposed as biomarker of response to immunotherapy in several tumors ( 60 ), although it is still not recognized as such in breast cancer ( 61 ). Another feature seen in our Basal samples, the expression of PD-L1, has been approved as biomarker for immune checkpoint blockade in TNBC ( 61 , 62 ) although it turned out to be ineffective in certain settings ( 63 ).…”

“…CYT was also proposed as biomarker of response to immunotherapy in several tumors ( 60 ), although it is still not recognized as such in breast cancer ( 61 ). Another feature seen in our Basal samples, the expression of PD-L1, has been approved as biomarker for immune checkpoint blockade in TNBC ( 61 , 62 ) although it turned out to be ineffective in certain settings ( 63 ). New prospective studies built under the example of the MPBCS might explore if the combination of both CYT and PD-L1 expression can be used as better predictive biomarkers of response to immunotherapy in Latin American TNBC patients.…”

Circulating proteins as predictive and prognostic biomarkers in breast cancer

“…The proteins found in blood have a long-standing history as cancer biomarkers, longer than several classes of biomarkers introduced more recently for liquid biopsy such as ctDNA, or miRNA. Blood profiling has recently gained momentum, especially in search for biomarkers useful in immuno-oncology and in monitoring of cancer patient response to neoadjuvant treatments [146][147][148][149]. However, despite technological improvements, protein detection sensitivity remains slightly poorer than ctDNA detection sensitivity.…”

Integrating Immunotherapy Into the Treatment Landscape for Patients With Triple-Negative Breast Cancer

“…29 To date, PD-L1 status remains the only biomarker prospectively validated in clinical trials to guide patient selection for first-line chemoimmunotherapy in advanced TNBC. 30…”