Page 114 - Read Online

Page 769 Wong et al. Cancer Drug Resist 2023;6:768-87 https://dx.doi.org/10.20517/cdr.2023.58

INTRODUCTION
Breast cancer is the most common cancer worldwide, accounting for 12.5% of all new cancer cases globally,
[1]
and is the leading cause of cancer mortality in women . In the year 2020, an estimated 2.3 million female
breast cancers were diagnosed globally, and about 685,000 women died from their disease . This number is
[2]
[2]
expected to grow to more than 3 million new cases diagnosed and 1 million deaths by the year 2040 .
With advances in our understanding of cancer biology, immuno-oncology has become an area of great
interest and extensive research. Cancer immunotherapy employs the use of cutting-edge technologies,
including immune checkpoint inhibitors (ICIs) such as those targeting Programmed Cell Death Protein-1
(PD-1), Programmed Cell Death Ligand-1 (PD-L1), and Cytotoxic T-Lymphocyte-Associated Antigen 4
(CTLA-4), and more recently, chimeric antigen receptor (CAR) T cell therapies. Other frontiers being
pushed in the realms of immunotherapy include the use of cancer vaccines , for cancer prevention, such as
[3]
vaccines for Human Papilloma Virus and Hepatitis B , as well as in cancer treatment, as in the case of
[4]
Sipuleucel-T for prostate cancer .
[5]
Since the first U.S. Food and Drug Administration (FDA) approval of ipilimumab, a CTLA-4 monoclonal
[6]
antibody, in 2011 for the treatment of metastatic melanoma , ICIs have transformed the treatment
landscape across multiple tumour types . There are now eleven FDA approvals for ICIs: two CTLA-4
[7]
inhibitors (ipilimumab, tremelimumab), five PD-1 inhibitors (pembrolizumab, nivolumab, cemiplimab,
dostarlimab, retifanlimab), three PD-L1 inhibitors (atezolizumab, avelumab, durvalumab), and one
lymphocyte-activation gene 3 (LAG-3) blocking antibody (retatlimab) . However, amongst the numerous
[6-9]
available approvals for ICIs, there are currently only two specific FDA approvals in the setting of breast
cancer, both for pembrolizumab in the subgroup of triple-negative breast cancer (TNBC), given in
[11]
combination with chemotherapy in the metastatic and neoadjuvant settings. Additional FDA approvals
[10]
that are tumour agnostic and apply to breast cancer include pembrolizumab and dostarlimab in breast
[12]
[13]
cancers displaying high microsatellite instability (MSI-H) or a deficiency in the mismatch repair protein
(dMMR) pathway. While one of the hallmarks of treatment with ICIs is its durable response that translates
to prolonged survival of these patients, admittedly, only a very small subset of patients benefit. In this review
article, we will first describe the evolution of ICI in the TNBC subtype, focusing on its approved
indications, before delving into the understanding of the resistance mechanisms towards ICIs, and how we
can harness such knowledge to develop new combination strategies.

EVOLUTION OF ICIS IN BREAST CANCER
Monotherapy ICIs in TNBC
Evidence for the use of ICIs in breast cancer first came from single-agent immunotherapy trials in the
metastatic setting, including the KEYNOTE-012 and KEYNOTE-086 studies. KEYNOTE-012 was a phase I
study that aimed to evaluate the role of single-agent pembrolizumab in patients with various advanced solid
tumours. In the cohort of TNBC who had progressed on a median of 2 lines of treatment, the objective
response rate (ORR) was 18.5% and 6-month progression-free survival (PFS) was 24.4%, 6-month and
[14]
12-month overall survival (OS) were 66.7% and 43.1%, respectively . The investigators observed that there
was a suggestion of response with increasing expression of PD-L1, albeit within a small sample size (n = 32).

KEYNOTE-086 was designed specifically to look at the role of pembrolizumab monotherapy in patients
with metastatic TNBC. This phase II multicohort study included all comers with ≥ 1 prior systemic
treatment for metastatic disease regardless of PD-L1 status (Cohort A) , and also patients with no prior
[15]
systemic treatment in the metastatic setting who had PD-L1 positive tumours defined as combined positive
score (CPS) ≥ 1 based on the Dako PD-L1 IHC 22C3 platform (Cohort B) . Comparing across cohorts,
[16]