Breast Cancer “Immunogram”

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This entry is adapted from the peer-reviewed paper 10.3390/cancers14092102

Triple-negative breast cancer (TNBC) has been considered for many years an orphan disease in terms of therapeutic options, with conventional chemotherapy (CT) still representing the mainstay of treatment in the majority of patients. Although breast cancer (BC) has been historically considered a “cold tumor”, exciting progress in the genomic field leading to the characterization of the molecular portrait and the immune profile of TNBC has opened the door to novel therapeutic strategies, including Immune Checkpoint Inhibitors (ICIs), Poly ADP-Ribose Polymerase (PARP) inhibitors and Antibody Drug Conjugates (ADCs).

triple-negative breast cancer immunotherapy biomarkers immune checkpoints inhibitors

1. Introduction

Rationale of Immune-Based Therapy in Breast Cancer

The complex interaction between cancer and immune cells and the understanding of the immune escape mechanisms led to the development of the immuno-oncology field.

In physiological conditions, there is a balance between proinflammatory and anti-inflammatory signaling regulated by immune checkpoints to prevent autoimmunity. These immune checkpoints are a set of inhibitory and stimulatory pathways that directly affect the function of immune cells. During cancer progression, the occurrence of several genomic mutations leads to the production of tumor neoantigens, which, in turn, could be recognized and destroyed by the immune system as being perceived as non-self. This dynamic process, called cancer immunoediting, is composed of three sequential phases (elimination, equilibrium, and escape), whereby the host immune cells activate the innate and adaptive responses to protect against tumor formation and shape tumor immunogenicity.

However, one of the hallmarks of cancer is the ability of malignant clones to evade immune-mediated destruction by multiple mechanisms, including impaired antigen presentation, upregulation of negative regulatory pathways and the recruitment of immunosuppressive cells populations. In particular, regulatory T (Tregs) cells in the tumor microenvironment (TME) display strong immune suppressive activity and are thus able to inhibit antitumor immune responses by means of cytokines activating inhibitory immune checkpoints.

In the last few years, three types of immunotherapeutic strategies have been employed and classified into: “passive”, including the infusion of monoclonal antibodies (moAbs), i.e., IgG isotypes that bind and neutralize a target tumor associated with or specific antigen yielding the lysis of cancer cells, or the systemic administration of recombinant cytokines; “active”, consisting of the administration of ICIs and vaccines, and “adoptive”, which exploits immune system cells to eliminate cancer cells, such as autologous T cell-based therapy ^[1] (Figure 1).

Figure 1. Immunotherapeutic strategies for the treatment of TNBC. Several studies are combining checkpoint blockades with multiple therapies, including traditional chemotherapy; PARP inhibitors; anti-VEGF/VEGF-R agents; anti-CTLA-4 antibodies or novel strategies including virotherapy, vaccination therapy, CAR T-cell or TCR T-cell therapy in order to overcome the mechanisms involved in the impairment of antitumor immune responses. Abbreviations: TCR: T-cell receptor; MHC-I: Major histocompatibility complex class I; MHC-II: Major histocompatibility complex class II; CTLA-4: Cytotoxic T-Lymphocyte Antigen 4; PD-1: Programmed cell death protein 1; PD-L1: Programmed death ligand 1; CAR: Chimeric antigen receptor; TAA: Tumor-associated antigen; TSA: Tumor-specific antigen; TCR:T cell receptor; VEGF: vascular endothelial growth factor; VEGF-R-: vascular endothelial growth factor receptor.

The outcome of ICI-based therapy largely depends on the immunogenic nature of the tumor, as demonstrated by the remarkable response and survival gain obtained in melanoma and small cell lung cancer treatment ^[2]^[3].

The introduction of immunotherapy in the treatment of breast cancer (BC) has been markedly delayed due to the low mutation rate and weak immunogenic potential compared to other malignancies.

However, recent evidence has demonstrated that the expression of immune genes, cytokines and the composition of the immune infiltrates are involved in BC occurrence and progression, supporting research efforts in the immunotherapy field ^[4]^[5].

A BC immune landscape is characterized by different degrees of immunogenicity, depending on the subtypes and disease settings (early vs. metastatic BC).

Both triple-negative breast cancer (TNBC) and human epidermal growth factor-positive (HER2+) tumors are commonly enriched in tumor-infiltrating lymphocytes (TILs) (20% and 16% of cases, respectively) ^[6] with high immune-related gene expression ^[7]^[8]. Conversely, hormone receptor-positive (HR+) breast tumors are generally considered as the immune silent cancer type due to the absence of tumor antigens, the low expression of Major Histocompatibility Complex class I (MHC-I) molecules and the inhibition of T helper 1 (Th1) effector cells ^[9].

Compared to primary BC, where anticancer immune surveillance is able to destroy malignant cells, metastatic disease is characterized by the activation of several immune evasion mechanisms resulting in an inert immune environment. These findings suggest that ICIs may be more active in early-stage BC rather than in the metastatic setting. Therefore, to increase immunogenicity in metastatic BC, several combination strategies have been proposed, including anti-PD-1/PD-L1 cytotoxic drugs or other immune modulatory molecules ^[10]^[11].

To date, two ICIs, atezolizumab and pembrolizumab, have received approval from the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) as first-line treatments, in combination with chemotherapy (CT), for TNBC patients with PD-L1-positive metastatic disease based on the results of the IMpassion130 ^[12] and KEYNOTE-355 ^[13] trials, respectively. In July 2021, after the results of KEYNOTE-522, pembrolizumab was also approved by the FDA in combination with CT as a neoadjuvant treatment and, after surgery, as a single agent for nine cycles for patients with high-risk stage II or III TNBC ^[14].

2. Breast Cancer “Immunogram”

Predictors of Response to Immune-Based Therapy

The survival benefit derived from the introduction of ICIs in cancer therapy is indisputable. Unfortunately, the majority of patients experience different clinical responses to the same immunotherapy protocol with a significant proportion of treatment failures.

Therefore, one of the major challenges in immune oncology is the identification of predictive biomarkers to determine BC patients eligible for immunotherapy, so as to reduce the cost of an ineffective treatment and to avoid the risk of serious immune-related adverse events (grades 3 and 4 in approximately 5–10% of patients).

Cytotoxic T Lymphocyte Antigen 4 (CTLA-4) and programmed cell death protein 1 (PD-1) were investigated first as immune checkpoints molecules.

CTLA-4 acts as a suppressive molecule able to inhibit both the proliferation and the effector functions of T cells ^[15]. CTLA-4 overexpression is observed in about 50% of BC patients, but its prognostic and predictive roles remain controversial ^[16]^[17]. To date, pilot clinical trials with anti-CTLA-4 antibodies (tremelimumab and ipilimumab) in BC have yielded negative results both in terms of progression-free survival (PFS) and overall survival (OS) ^[18].

PD-1 is an inhibitory receptor acting as a suppressor of both adaptive and innate immune responses and is expressed on activated T-lymphocytes, particularly on tumor-specific cells, as well as on natural killer (NK) and B lymphocytes, macrophages, dendritic cells (DCs) and monocytes ^[19]. Programmed death ligand-1 (PD-L1) is a 40 kDa type 1 transmembrane protein expressed on human cells that is specific for the PD-1 receptor on the surface of immune effector cells. The PD-1/PD-L1 interaction plays a crucial role in maintaining self-tolerance and in the regulation of inflammation through T-cell function inhibition ^[20]. Not surprisingly, engagement of this ligand-receptor pair represents an adaptive immune mechanism of cancer cells to escape antitumor responses ^[21].

In BC, PD-L1 is more expressed in stromal immune cells (ICs) compared to tumor epithelium and is commonly associated with unfavorable clinicopathologic features (i.e., a large tumor size and poorly differentiated histological grade, high Ki67), high TIL counts, TNBC subtype and HER2+ status ^[22]. Despite its association with aggressive tumor characteristics, the upregulation of PD-L1 in ICs is associated with a better survival in BC ^[23]. Clinical trials evaluating ICIs have reported promising results in PD-L1-positive patients with advanced TNBC ^[12]^[13].

Conversely, in the neoadjuvant setting, immunotherapy seems to provide benefits regardless of the PD-L1 status ^[24]. Although the immune-based strategy has shown exciting therapeutic benefits for patients with PD-L1-positive metastatic TNBC (mTNBC), several studies have demonstrated that the PD-L1 status is insufficient for identifying responder patients ^[25]. Moreover, a recent analysis of the Tumor Cancer Genome Atlas (TCGA) revealed that PD-L1 positivity is only weakly associated with immunotherapy efficacy ^[26]. These discrepancies could be attributable to the lack of standardized PD-L1 assays and antibodies, as well as to the temporally and spatially heterogeneity in PD-L1 expression ^[27]^[28]^[29]^[30]^[31]^[32].

Several PD-L1 assays have been developed with different scoring systems, cutoffs and definitions to define PD-L1 positivity: SP142 (Roche Tissue Diagnostics, Tucson, AZ, USA), SP263 (Roche Tissue Diagnostics), 22C3 (Agilent Technologies Inc., Santa Clara, CA, USA) and 28-8 (Agilent Technologies Inc.).

Due to these drawbacks, the post hoc analysis of IMpassion130 assessed the analytical and clinical concordance of the DAKO 22C3, VENTANA SP142 and VENTANA SP263 assays.

The VENTANA SP142 and VENTANA SP263 assays assessed the PD-L1 expression on ICs with a 1% threshold. DAKO 22C3 evaluated the PD-L1 positivity by using a combined positive score (CPS), defined as the number of PD-L1-stained cells (tumor cells, lymphocytes and macrophages) divided by the total number of viable tumor cells multiplied by 100. These immunohistochemistry assays were not interchangeable, since the positive percentage agreements (PPA) between VENTANA SP142 IC and SP263 IC and between VENTANA SP142 IC and DAKO 22C3 CPS were 97.5% and 97.9%, respectively ^[33]. Recently, the VENTANA SP142 platform has been shown to display a lower sensitivity in detecting PD-L1 positivity on both tumor and immune cells with respect to DAKO 22C3 and VENTANA SP263 (46%, 81% and 75%, respectively) ^[33]^[34].

Moreover, the PD assessment may be affected by different tissue fixation/preservation methods, as inferred by higher PD-L1 scores in frozen tissues compared to their matched formalin-fixed paraffin-embedded samples ^[35].

Due to the spatial and temporal heterogeneity of PD-L1, it is unclear whether the evaluation should be assessed on primary or secondary lesions.

Primary BC has been reported to show higher rates of PD-L1 expression than metastatic sites, likely due to immune escape mechanisms occurring during disease progression ^[28]^[36]. Moreover, the IC assessment of metastatic sites revealed the highest prevalence of PD-L1 positivity on lymph nodes and lungs, as opposed to the liver, where an immunosuppressive microenvironment has been identified ^[37]^[38]. The PD-L1 status is also strongly modulated by treatment, with a conversion rate (from positive to negative and vice versa) ranging from 25 to 30% over time ^[39]. In particular, after neoadjuvant chemotherapy (NACT), PD-L1 expression has been demonstrated to be considerably expressed on a residual disease sample ^[40] consistent with the observations of CT inducing an adaptive immune response ^[41].

Since PD-L1 cannot act as a comprehensive and independent biomarker in clinical practice, several efforts have been made to identify additional biomarkers potentially able to effectively predict the treatment response to ICIs, such as the abundance of CD8⁺ TIL infiltration, tumor mutational burden (TMB), mismatch repair deficiency (dMMR), microsatellite instability (MSI) and PD-1 copy number alteration (CNA).

The clinical validity of TILs in BC is now well-established. TILs are mononuclear ICs categorized as stromal compartment TILs (sTILS) and intra-tumoral compartment TILs (iTILs), consisting of different lymphocyte subtypes, mostly T cells (cytotoxic CD8⁺ and helper CD4⁺), admixed with B cells, NK cells and macrophages ^[42]^[43].

TILs recognize neoantigens generated after cancer cell death and elicit an antitumor response through the interaction of distinct T-cell receptors (TCR) with specific neoantigen-derived epitopes presented by MHC molecules ^[44].

Lymphocyte predominant breast cancers (LPBC), characterized by the presence of 50–60% TILs, are associated with more favorable survival outcomes and a higher probability of a pathological complete response (pCR) after neoadjuvant therapy ^[45]. The prevalence of TILs is a dynamic event that is stage- and site-dependent (high or low in the case of early or advanced stages, respectively, and the variably detected depending on the sites of BC metastases, being the highest in lung metastases and lowest in liver and skin lesions) ^[36]. Furthermore, the production of interferon γ (IFN-γ) by activated TILs leads to PD-L1 and MHC-I upregulation, suggesting a crucial role for IFN-γ signaling in antitumor immune responses ^[46].

Since PD-L1 expression and TIL levels are strongly correlated with each other, the simple morphological evaluation of TILs may represent a surrogate of the activated host antitumor immune response ^[47].

Exploratory analyses of recent clinical trials have suggested that TILs are associated with the response to both cytotoxic and immune therapies, particularly in TNBC patients. These findings support the clinical utility of TILs in predicting the beneficial impact of immunotherapy in early and advanced TNBC settings; however, due to the retrospective nature of these data, further confirmatory independent prospective studies are needed ^[48].

A further promising predictor of the response to ICIs is represented by TMB, defined as the measurement of the amount of nonsynonymous mutations per coding area of a tumor genome. These mutations can be transcribed and translated, leading to the production of misfolded proteins (neoantigens) that can be recognized as non-self by T cells, thereby resulting in strong effector cell responses. Compared to other malignancies such as melanoma, lung and colorectal cancer, BC displays a lower mutation load (roughly one mutation per Mb). Indeed, a high TMB, which indicates a “hot tumor phenotype”, is found in only 3.1% of BCs and is more frequently detected in the HR-negative subtype and in older patients. These tumors, characterized by a high degree of immune infiltration, are associated with improved survival outcomes, regardless of tumor stage, molecular subtype, PD-L1 status, age and treatment schedule ^[49]. In BC, a high TMB is more likely associated with the MMR pathway or homologous recombination repair system deregulation, alterations in DNA polymerase genes (POLE/POLD1) and the APOBEC mutation signature ^[50]. Of note, compared to early BC, more advanced tumors generally display a higher TMB, probably related to the accumulation of genomic instability during disease progression or treatment-associated selective pressure, and less abundant TIL levels reflecting cancer immune escape mechanisms ^[48]^[51].

A significant correlation between a high TMB and response to ICIs has been reported in several cancers, including urothelial carcinoma, lung cancer, melanoma and human papilloma virus (HPV)-negative head and neck squamous cell carcinoma ^[52]. Few data are available about TMB and the response to immunotherapy in BC. In the retrospective analysis of the TAPUR (Targeted Agent and Profiling Utilization Registry) trial, the cohort of metastatic BC patients with a high TMB (defined as at least nine mutations per Mb, according to a FoundationOne test or another TAPUR-approved test) treated with pembrolizumab showed an objective response rate (ORR) and a disease control rate (DCR) of 21% and 37%, respectively ^[53].

Furthermore, in the KEYNOTE-119 trial, patients with previously treated mTNBC and TMB ≥ 10 mutations per Mb had tendentially a better outcome with pembrolizumab than with CT ^[54]. Conversely, in a large analysis including 1662 patients affected by different advanced malignancies receiving at least one dose of ICIs, no association was observed between higher TMB and improved survival in the subgroup of BC patients. Furthermore, a subgroup analysis of the GeparNuevo trial suggested an increased likelihood of pCR after NACT in the case of a high TMB independently from the addition of durvalumab ^[55]. These divergent results and the absence of both a well-established method of evaluation (targeted NGS panels or whole-exome sequencing) and optimal threshold to define high vs. low mutational burdens make TMB unable to predict the response to immunotherapy in BC.

During DNA replication, several errors such as the insertion, deletion and misincorporation of bases may occur. These are more frequent in non-coding short-tandem repeats in the genome known as microsatellites and are corrected by MMR proteins. When MMR genes are mutated or epigenetically silenced, they fail to repair post-DNA replicative mistakes and may lead to the MSI-high (MSI-H) phenotype characterized by alterations in the length of microsatellite regions ^[56]. The accumulation of mutations carried by MSI-H tumors elicits TIL immune-specific antitumor responses ^[57]. Therefore, MSI-H/dMMR tumors are more prone to be responsive to ICIs. Based on this evidence, pembrolizumab FDA’s approval included all solid tumors harboring this intrinsic genetic scare. The dMMR feature is extremely rare in BC, accounting for only 1 to 2% of cases. The reported low percentage of dMMR BC may be influenced by the absence of a Companion Diagnostics assay (CDx) and/or tumor-specific guidelines for a MMR analysis and the different testing methods employed, such as direct sequencing of microsatellite markers, next-generation sequencing (NGS) and immunohistochemistry (IHC) for the four MMR proteins. In BC, MMR protein loss is more commonly detected than MSI; therefore, IHC for the MMR proteins and MSI testing are not interchangeable, as in other tumor types ^[58]. In this context, the expression analysis of phosphatase and tensin homolog (PTEN), a key tumor suppressor involved in cell growth, proliferation and survival but also implicated in the MMR and overall DNA damage response, has been proposed to identify MMR-proficient (pMMR) breast tumors. Despite these limitations, the predictive value of MMR deficiency has been demonstrated in two reports evaluating metastatic triple-negative and luminal BC patients treated with nivolumab and pembrolizumab, respectively ^[59]^[60]^[61].

BRCA1 and BRCA2 are two suppressor genes involved in the repair of DNA double-stranded breaks. Mutations of BRCA genes are reported in about 5% of all diagnosed BC patients and are generally associated with increased TILs and higher PD-L1 and CTLA-4 gene expression than tumors with wild-type genes, suggesting an increased likelihood of a positive ICI response ^[62]. In the IMpassion130 trial, about 15% of the enrolled patients had BRCA mutations. In a subgroup analysis including PD-L1-positive patients, those harboring BRCA1 or BRCA2 mutations were shown to benefit from the immunotherapy combination more significantly than the wild-type subset. Therefore, although these genes cannot be considered independent biomarkers, they nonetheless contribute to tailoring the ICI approach ^[63].

During the 2020 ESMO Breast Cancer Virtual Meeting, an increase in the number of PD-L1/CD274 genes measured by CNA was proposed as a predictive marker for PD-L1 inhibitor efficacy. An exploratory translational analysis of the SAFIR-02 IMMUNO trial showed a higher efficacy of durvalumab for patients with PD-L1 copy gain (three or four copies) or amplification (>four copies) in all subtypes, as well as in TNBC ^[64].

Despite how PD-L1 CNA seems to be a promising biomarker, further analyses are needed to understand whether PD-L1 amplification is associated with overexpression at the protein level and the underlying biological mechanism.

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