Biologically, TNBCs are highly heterogeneous and until recently had no informative biomarkers for targeted therapy [1], leaving cytotoxic chemotherapy as the only available systemic approach.

However, among breast cancer subtypes, TNBC has characteristics that may make it more responsive to treatment with immunotherapy. These characteristics include a higher mutational burden, where despite a high range of variance within each tumor type, TNBC was found to have more median mutations than HER2-positive or luminal-type hormone receptor positive tumors [2]. Higher tumor mutational burden can lead to a higher frequency of immunogenic mutations [3, 4], and has been described as a marker of improved survival following immunotherapy across multiple tumor types [5, 6]. TNBC also exhibits higher mean quantities of tumor infiltrating lymphocytes (TILs) relative to other breast cancer subtypes. In early-stage TNBC, TIL count is associated with improved survival, reduced recurrence risk, and increased likelihood of response to neoadjuvant chemotherapy [7,8,9]. TIL count has also been described as a potential biomarker of immunotherapy response [10].

TNBC also has a higher rate of programmed death ligand 1 (PD-L1) expression relative to other breast cancer subtypes, providing a potential therapeutic target with antibody inhibitors of programmed death 1 (PD-1) or PD-L1 [11, 12]. Recently, the Food and Drug Administration (FDA) approved atezolizumab (anti-PD-L1) for use in combination with nab-paclitaxel for PD-L1-positive advanced TNBC. While immune checkpoint blockade is the most studied form of immunotherapy for TNBC, other modalities are also being evaluated. In this review, we aim to examine the current role of immunotherapy in TNBC, present the modalities of immunotherapy currently being evaluated, and discuss the future of immunotherapy in the clinical management of TNBC.

Immune Checkpoint Blockade

A number of anti-PD-1/L1 antibodies have been evaluated in metastatic TNBC as monotherapy (Table 1). These agents are generally well tolerated and may induce durable responses; however, responses appear restricted to a minority of patients. For example, KEYNOTE-012 was a phase Ib study of pembrolizumab monotherapy in PD-L1-positive patients (PD-L1 ≥ 1% by IHC), which demonstrated an objective response rate (ORR) = 18.5%, with 3 responders with ongoing response ≥ 1 year. Notably, the population was heavily pre-treated with a median number of prior lines of systemic therapy in the metastatic setting of 2, with 25% of patients having received ≥ 5 lines [18]. A follow-up phase II study evaluated pembrolizumab according to PD-L1 status and line of therapy, with cohort A including pre-treated patients (n = 170, 62% PD-L1-positive), and cohort B including first-line PD-L1-positive patients (n = 84). Cohort A reported a 5.3% ORR (5.7% among PD-L1-positive), whereas cohort B reported a 21.4% ORR. Responses were durable, with a median duration of response of 10.4 months in cohort B (not reached in cohort A) [16•, 20]. Of note, a phase III comparison of 2nd/3rd-line pembrolizumab monotherapy versus investigator’s choice chemotherapy (capecitabine, eribulin, gemcitabine, or vinorelbine) failed to meet its primary endpoint of overall survival [21]. The pembrolizumab data suggest that anti-PD-1/L1 is more effective in earlier lines of therapy. This finding was confirmed in the phase Ib evaluation of atezolizumab monotherapy, whereby first-line ORR was 24% (n = 21), versus 6% in later lines (n = 94) [13]. In this trial, response also appeared dependent on PD-L1 status, with PD-L1-positive tumors having an ORR of 12%, versus 0% for PD-L1-negative tumors. This trial also confirmed the durability of response, with median response in the first-line setting lasting 21 months.

Table 1 Reported trials of immune checkpoint blockade monotherapy and in combination with chemotherapy in the metastatic setting for TNBC

Immune Checkpoint Blockade with Chemotherapy

Chemotherapy is known to have various immunomodulatory effects, with growing evidence that the restoration of host immunosurveillance may be part of the benefit seen with conventional chemotherapies [22,23,24]. IMpassion130 was a registrational phase III trial that evaluated chemotherapy (nab-paclitaxel) plus atezolizumab versus placebo in first-line metastatic/advanced TNBC [17•]. In the intention-to-treat (ITT) analysis at a median follow-up of 12.9 months, median PFS was 7.2 months in the atezolizumab plus nab-paclitaxel arm (n = 451) versus 5.5 months in the placebo plus nab-paclitaxel arm (n = 451) (p = 0.0025). In a pre-specified subgroup analysis, improvements were more pronounced in PD-L1-positive tumors (PFS, 7.5 vs. 5.0 months). In the ITT overall survival (OS) analysis, OS was 21.3 months in the atezolizumab arm versus 17.6 months in the chemotherapy alone arm, which did not meet statistical significance (p = 0.08). Among PD-L1-positive tumors, the median OS was 25.0 months versus 15.5 months. The hazard ratio was reported of 0.62 (95% CI 0.45–0.86); however, formal p value testing could not be performed because it was not designated as a pre-specified primary outcome in the setting of the ITT OS being non-significant. This data led to the FDA approval for atezolizumab plus nab-paclitaxel only for PD-L1-positive tumors. Updated OS data from the second interim analysis at median follow-up of 18.0 months showed an OS of 21.0 months in the atezolizumab plus nab-paclitaxel arm versus 18.7 months in the nab-paclitaxel alone arm (p = 0.0777) in the ITT population. In the PD-L1-positive subgroup, OS was 25.0 months versus 18.0 months, for a hazard ratio of 0.71. This updated data showed persistent benefit in overall survival in the PD-L1-positive population [25].

IMpassion130 was the first randomized trial to demonstrate improved outcomes of anti-PD-1/L1; however, the trial leaves a number of questions unanswered. No atezolizumab monotherapy arm was included in the study, and it is unknown whether patients could equally benefit from a sequential approach of atezolizumab followed by nab-paclitaxel at progression. One appealing future direction might be to employ biomarkers or risk stratification factors (LDH, visceral disease) to identify a subset of patients most likely to benefit from monotherapy. In the monotherapy trials, responses have been worse in patients who have had multiple prior lines of therapy. In addition, the inclusion of patients with elevated LDH was thought to have played a role in the response rate seen in KEYNOTE-012/086, with no responses noted in patients with elevated LDH in KEYNOTE-012 [18]. Investigators commented on the possibility that these patients had more aggressive, rapidly growing tumors compared with patients with lower baseline LDH. Other poor prognostic factors included the presence of visceral disease and liver metastases. However, in the IMpassion130 subgroup analysis, subjects with liver metastases had a similar improvement in benefit with the addition of atezolizumab to nab-paclitaxel [17•].

A second unanswered question is whether patients with early relapse could benefit from combination therapy. The ongoing IMpassion132 trial will evaluate patients who would have been IMpassion130 ineligible, enrolling subjects with relapse ≤ 12 months from receipt of curative-intent chemotherapy to receive atezolizumab or placebo with investigator choice gemcitabine + carboplatin or capecitabine. The primary endpoint will be overall survival [26]. In the ongoing KEYNOTE-355 study, subjects with de novo metastatic disease or relapse > 6 months from receiving curative-intent therapy receive investigator’s choice chemotherapy (gemcitabine/carboplatin or nab-paclitaxel or paclitaxel) with or without pembrolizumab [27]. In a recent phase Ib trial, patients with early relapse < 12 months from curative-intent chemotherapy experienced 38% ORR (n = 3/8) to capecitabine plus pembrolizumab [28].

A third unanswered question is whether alternative chemotherapy backbones will be safe or effective. Chemotherapies have varied mechanisms of immunomodulation and have been the subject of extensive review [22,23,24]. Phase III trials of various combinations are ongoing, including the aforementioned KEYNOTE-355 study of investigator’s choice chemotherapy (gemcitabine/carboplatin or nab-paclitaxel or paclitaxel) with or without pembrolizumab and a number of small phase Ib/II trials have demonstrated safety and encouraging activity of combinations including capecitabine, eribulin, doxorubicin, cisplatin, and paclitaxel, among others (Table 1). The TONIC study aimed to compare the immunomodulatory effects of induction chemotherapy followed by nivolumab (anti-PD-1). The overall ORR = 20%, with the highest response rates noted in the cisplatin (ORR = 23%) and doxorubicin (ORR = 35%) cohorts. Analysis of initial and post-induction biopsies showed upregulation of immune-related genes in PD-1/PD-L1 and T cell cytotoxicity pathways in the doxorubicin and cisplatin cohorts [29•]. In addition to exhibiting immunostimulatory effects, one must also consider the long-term lymphodepleting effects of chemotherapy. In a recent comparison of pembrolizumab plus capecitabine or paclitaxel, both chemotherapy backbones were associated with sustained and profound decay of T cell populations over time, including CD4+ and CD8+ T cell populations [28]. Lymphodepletion has been hypothesized as one potential mechanism to explain the decline in anti-PD-1/L1 efficacy in later lines of therapy in TNBC.

Immune Checkpoint Blockade in the Neoadjuvant and Adjuvant Settings

Preliminary neoadjuvant studies of anti-PD-1/L1 have been encouraging, with combination approaches being well tolerated and associated with increases in pathologic complete response (pCR) rate, a known surrogate of overall survival in TNBC (Table 2) [32]. KEYNOTE-173 was a phase Ib study of pembrolizumab with various regimens/dosings of platinum and taxanes as neoadjuvant therapy, followed by 4 cycles of doxorubicin + cyclophosphamide prior to surgery in patients with stage II-III TNBC [33]. In this small study, pCR rates of various chemotherapy/pembrolizumab combinations ranged from 60 to 80%, with the best responses observed in carboplatin-containing cohorts. These data provide rationale for a phase III trial evaluating curative-intent chemotherapy (carboplatin + “ACT” doxorubicin, cyclophosphamide, paclitaxel) + placebo versus pembrolizumab (KEYNOTE-522) [34]. I-SPY2 is an adaptive phase II study that evaluated pCR rates of ACT with or without pembrolizumab. A total of 69 subjects were randomized to combination therapy and showed a 40% increase in the estimated pCR of 60% from 20% in the chemotherapy only control. There are concerns that the pCR rate in the control group was lower than expected; however, the study design permitted investigators to switch therapy or advance to surgery in the setting of clinical non-response, and these subjects were considered treatment failures per the ITT analysis. Of note, dramatic increases in pCR were observed with pembrolizumab even in the context of potential immunosuppressive effects of steroids administered with paclitaxel [30]. Additional neoadjuvant studies are ongoing (Table 3).

Table 2 Reported trials of immune checkpoint blockade in the neoadjuvant setting in TNBC
Table 3 List of notable ongoing trials evaluating combination therapies with immune checkpoint blockade in TNBC

One unanswered question is whether treatment sequencing can modulate response. GeparNuevo was a phase II study randomizing subjects to neoadjuvant chemotherapy plus durvalumab (anti-PD-L1) versus placebo [31]. Approximately 117 patients received a 2-week durvalumab/placebo induction prior to commencing chemotherapy. The study failed to meet its endpoint, with 53.4% of patients in the durvalumab arm (n = 88) and 44.2% in the placebo arm (n = 86) achieving pCR (p = 0.287). However, in an unplanned analysis, subjects treated with induction therapy had greater difference in pCR rate (61% vs. 41.4%), highlighting the possibility that anti-PD-L1 pre-treatment may enhance response. A related question is whether anti-PD-1/L1 would be effective in the adjuvant setting. In murine models, neoadjuvant immunotherapy was superior to adjuvant immunotherapy in reducing metastatic lesions [35•]. However, treating in the adjuvant setting affords the opportunity to select patients at higher risk of recurrence based upon suboptimal chemotherapy response. A number of adjuvant anti-PD-1/L1 studies are ongoing, including IMpassion030, a phase III study of adjuvant atezolizumab versus placebo in combination with chemotherapy (NCT03498716), and SWOG 1418, a phase III study of adjuvant pembrolizumab versus placebo for subjects experiencing non-pCR following neoadjuvant chemotherapy (NCT02954874).

Dual Immune Checkpoint Blockade

There is interest in evaluating the combination of anti-PD-1/L1 with antibodies against other checkpoints such as cytotoxic T lymphocyte antigen 4 (CTLA-4). Ipilimumab (anti-CTLA-4) is FDA-approved in combination with anti-PD-1 (nivolumab) for the indication of melanoma [36, 37], lung cancer, and renal cell carcinoma, and is thought to enhance response by blocking suppressive CTLA-4 signaling on T cells, and/or by depleting CTLA-4-expressing T-regulatory cells [38]. Studies in breast cancer with dual immune checkpoint blockade have been limited, though preclinical studies have shown promise with this combination in TNBC [39]. In a pilot study of anti-PD-L1 (durvalumab) plus anti-CTLA-4 (tremelimumab), the estimated ORR for TNBC was 43% (n = 4/7) [40]. A study of dual immune checkpoint blockade using nivolumab and ipilimumab with androgen receptor blockade in metastatic HR-positive and TNBC is currently enrolling [41]. Furthermore, a number of early phase studies are ongoing to evaluate the safety and efficacy of anti-PD-1/L1 with other immune checkpoint agents, including modulators of macrophage or natural killer cell activity.

Immunotherapy with Locoregional Therapy

Radiation is frequently employed in TNBC, either in the adjuvant setting following surgical resection or in the metastatic setting to palliate symptoms. The abscopal effect has long been described in radiotherapy whereby regression of non-radiated lesions occurs following local radiotherapy, a phenomenon thought to be related to a systemic anti-tumor immune response [42]. The synergistic effect of radiotherapy with immunotherapy may be related to release of tumor antigens and DAMPs that can activate an immune response [43]. In a phase II study, pembrolizumab plus radiotherapy in metastatic TNBC was well tolerated in a heavily pre-treated population. Eight of the 17 patients enrolled could not be evaluated for response due to rapid tumor progression and death; however, 33% of evaluable patients (n = 3/9) experienced partial response, with one response up to 31 weeks, and another ongoing at 22 weeks, for an ORR = 17.6% [44]. Multiple trials are underway to evaluate the combination of immunotherapy with radiotherapy in TNBC, in the metastatic setting with pembrolizumab (NCT02730130) and nivolumab (NCT02499367), and in pre-operative settings with pembrolizumab (NCT03366844) and durvalumab (NCT03872505). Studies are also underway comparing single versus multi-fraction stereotactic ablative body radiotherapy with atezolizumab in advanced TNBC (NCT03464942). In addition to radiotherapy, cryoablation has been evaluated in combination with immunotherapy. A pilot study of pre-operative cryoablation and single-dose of ipilimumab found to be safe and associated with intra-tumoral and systemic immune effects [45]. A phase II study of peri-operative ipilimumab + nivolumab + cryoablation after taxane-based neoadjuvant chemotherapy in resectable TNBC is ongoing (NCT03546686).

Immunotherapy with Other Targeted Therapies

Approximately 15% of TNBCs have alterations in the Ras/MAPK pathway. In preclinical TNBC models, MEK inhibiters were clinically active in combination with anti-PD-1/L1 inhibitors, and associated with MHC and PD-L1 upregulation [46]. The phase II COLET study evaluated the MEK 1/2 inhibitor cobimetinib with atezolizumab plus taxane in TNBC, with an ORR = 34% (11/32•) with paclitaxel, and an ORR = 29% (9/31) with nab-paclitaxel. Higher response rates were noted in PD-L1-positive tumors (ORR 44%/33%) [47]. Additional studies are underway (NCT03106415, NCT03971409).

BRCA1/2 mutations are found in 20–30% of TNBCs [48••, 49], causing deficiency in DNA repair and sensitivity to DNA-targeting cytotoxic agents (cisplatin/carboplatin) and inhibitors of the poly(ADP-Ribose) polymerase 1 enzyme (PARP) [48••, 50, 51]. Furthermore, PARP inhibitors can upregulate PD-L1 and enhance cancer-associated immunosuppression, and therefore, combination with anti-PD-1/L1 agents is of interest [52]. TOPACIO/KEYNOTE-162 was a study combining the PARP inhibitor niraparib with pembrolizumab in TNBC, with initial data on 45 patients showing an ORR = 29%, with a disease control rate of 49%. Among BRCA mutant patients, the ORR was 67% with a disease control rate of 75% [53]. Studies with durvalumab plus olaparib in metastatic TNBC are also ongoing (NCT03167619, NCT03801369).

The androgen receptor has also been identified as a potential target for TNBC, with approximately 55% of TNBC having some degree of upregulation of the androgen receptor [54]. Early trials have shown tolerability and clinical benefit with androgen receptor blockade in TNBC, with a clinical benefit rate of 35% at 16 weeks in one study, with higher rates noted in patients who were positive for an androgen-related gene signature [55]. Preclinical studies have shown that androgen receptor blockade may augment thymic production of T cells, leading to interest in combination with immunotherapy [56]. A phase II study of pembrolizumab with GTx-024, a nonsteroidal selective androgen receptor modulator, showed that treatment was well tolerated, with 2 partial responses and 2 with stable disease out of 16 patients, and is ongoing [57]. Additionally, a phase II study combining bicalutamide with dual immune checkpoint blockade with nivolumab plus ipilimumab is currently underway (NCT03650894) [41].

More than 3000 next-generation immunomodulatory agents are in clinical development either as monotherapy or in combination with anti-PD-1/L1 to increase efficacy. As of this review, no phase II/III studies have confirmed clinical benefit of this approach in TNBC. However, going forward, next-generation biomarkers (such as DNA/RNA deep sequencing and multispectral TIL analysis) may provide more nuanced understanding of immune profiles and pharmacodynamic effects of immunotherapy agents, and could ultimately be used to personalize combination therapy and improve likelihood of clinical benefit.

Cellular Therapy

T cells have been identified as key players in potentiating anti-tumor immunity, and are being investigated in TNBC. Adoptive cell therapy is a form of immunotherapy that involves isolating T cells from a patient, enriching for tumor-specific clones (sometimes by selecting for reactivity against mutated proteins), expanding and activating these cells ex-vivo, and then autologously administrating them back to the patient [58, 59]. Recently, a subject with chemo-refractory hormone receptor–positive breast cancer experienced a complete response with this approach, and evaluation is ongoing in TNBC patients [60]. An alternative adoptive cell therapy is chimeric antigen receptor (CAR) T cell therapy, whereby T cells are genetically engineered to express receptors against a specific target (such as CD19 for B cell malignancies). Target selection is critical for the success and safety of this approach, as even low target expression on non-malignant tissue can lead to substantial toxicity. Severe allergic reactions, cytokine release syndrome, and neurologic toxicities have been documented with cellular therapies, often requiring inpatient administration and monitoring [61]. Potential targets under investigation for cellular therapy in TNBC include MUC1 [62], NKG2D [63], AXL [64], TEM8/ANTXR1 [65], FRα [66], mesothelin (NCT02892114), and ROR1 (NCT02706392). Preliminary data of 4 TNBC patients treated with ROR1+ CAR-T cells has been presented, with 2 patients demonstrating stable disease (one at 15 weeks, one at 19 weeks), and one patient with partial response after a 2nd infusion [67].


A number of cancer vaccines are in development for TNBC, and aim to facilitate anti-tumor immunity by directing the immune response against tumor-associated antigens (NCT03674827, NCT03387085, NCT02593227, NCT03012100) [68]. In addition, there is great interest in the combination of vaccines with immune checkpoint blockade to enhance the ability of vaccines to elicit a T cell response (NCT03362060, NCT02432963, NCT03761914, NCT02826434, NCT03199040, NCT03606967, NCT03289962). Early data on peptides as vaccines for metastatic cancer showed low response rates, with a 2.9% ORR in a combined evaluation of 381 patients with metastatic cancer receiving peptide vaccines [69]. More encouraging results have come from personalized peptide vaccination (PPV), a type of vaccine where antigens are selected from a pool of different peptides based on pre-existing host immunity. Currently, a maximum of 4 peptides are selected among a group of 31 different HLA class-I peptide candidates, based on HLA typing and pre-existing immune responses to each candidate. Early trials in multiple different tumor types have shown a response rate of 9.9% and a disease control rate of 42.9% in a group of 500 patients with advanced cancer [70]. PPV has been evaluated in TNBC and was safe and potentially effective, with a median PFS of 7.5 months and median OS of 11.1 months in metastatic TNBC, with 1 complete response and 1 partial response noted in a cohort of 18 patients [71]. Additional small studies are ongoing in TNBC (NCT02427581). Dendritic cell (DC) vaccines have also been found to be an effective strategy in multiple cancer types, most notably prostate, and evaluation in TNBC has found safety and potential efficacy as well [72, 73].

Autophagy-based vaccines are being developed for TNBC. In short, cancer cells are manipulated ex vivo with proteasome inhibitors and other modulators of autophagy to create a vaccine against tumor-associated proteins as well as short-lived proteins and organelle fragments that would be otherwise degraded [74]. Autophagy-based vaccines have been shown preclinically to be effective not only in the autologous setting where the vaccine was made from a host’s own tumor but also in an allogenic setting whereby the vaccine is made by other tumor cell lines, allowing for creation of an “off-the-shelf” vaccine that could be used for many different patients [74]. Based upon preclinical efficacy in mammary carcinomas, a trial of vaccine + anti-PD-1 + T cell agonist (anti-OX40) is underway (NCT02737475).

The Role of Biomarkers in Immunotherapy for Breast Cancer

The results of the IMpassion130 highlight the need for immune-based biomarkers in TNBC, as larger improvements in PFS and OS were noted in the PD-L1-positive subgroup compared with the ITT population. However, it must be noted that PD-L1 positivity may vary according to assay and cutoff and has not been consistently predictive for anti-PD-1/L1 response [75]. One unanswered question is whether it is more relevant to test PD-L1 on tumor cells or immune cells or both, with preclinical data supporting the relevance of both [76]. IMpassion130 used a definition of PD-L1 positivity of ≥ 1% PD-L1 expression on immune cells, whereas other clinical trials employ combined tumor/immune cell scores or other approaches. Various PD-L1 assays (Dako 22C3, SP142, SP263) may provide incongruous results on the same tumor [77•]. In particular, the SP142 assay used in the IMpassion130 trial appears to be less sensitive than Dako 22C3 and SP263, with a lower percentage of tumors testing PD-L1-positive. It is unknown whether tumors that are PD-L1-negative by SP142 but PD-L1-positive by other assays are biologically distinct entities, and whether they would benefit from anti-PD-1/L1.

Another biomarker of interest is the stromal TIL score, which is known to be prognostic and predictive in the setting of curative-intent chemotherapy. In the IMpassion130 analysis, stromal TIL score or CD8+ T cell count did not independently predict benefit to atezolizumab [78]. There are some considerations as to why stromal TILs were unable to correlate with benefit. TILs have been noted to be decreased in metastatic compared with early breast cancers [79]. There also appears to be a scarcity of stroma in metastatic breast cancer specimens and whether this could contribute to an inability to detect an association between stromal TILs and OS benefit is a consideration. Assessment of KEYNOTE-086 patients who received pembrolizumab monotherapy in metastatic TNBC showed higher TILs could identify patients who were more likely to respond to therapy. TIL level was higher in the previously untreated population, and higher TIL levels were associated with significantly improved ORR and disease control rates [80].

Tumor mutational burden (TMB) has been correlated with response to immunotherapy in multiple cancer types; however, high TMB is uncommon in breast cancer [5]. In one study, only 3.1% of breast carcinomas had high TMB (> 20 mutations/Mb), compared with 39.7% of melanoma and up to 24.3% of lung carcinomas. In another study of TMB in 3689 breast cancer samples, 4.2% of TNBC samples were found to have a high TMB [81]. TMB may be a useful biomarker in TNBC patients with high TMB, but may also exclude patients who may benefit from immunotherapy. Extensive research is ongoing to develop pipelines for identifying specific mutations that may be associated with anti-tumor immune response [5, 6]. Mismatch repair deficiency is also predictive of benefit with anti-PD-1 therapy, and pembrolizumab is FDA-approved for solid tumors with high microsatellite instability or mismatch repair deficiency [82]. However, these defects are uncommon in TNBC, with one analysis estimating 0.7% in TNBC [83, 84]. A number of novel biomarkers are being explored in immunotherapy, such as serum proteins, peripheral blood immune cells, and host genomic factors [85].


Immunotherapy has emerged as a promising treatment modality for TNBC. Initial trials have established a role for anti-PD-L1 in the first-line metastatic setting in combination with chemotherapy. Ongoing trials will clarify the role of anti-PD-1/L1 as monotherapy, in later lines of therapy, or in combination with other therapies. Additional work is ongoing to identify clinical factors (LDH, liver metastases) and biomarkers to optimize use of these agents. Multiple trials are also underway evaluating which combination of therapies may work best with immune checkpoint blockade including combinations with chemotherapy, radiotherapy, cryotherapy, vaccines, and other targeted agents (Table 3).

With factors such as TILs and PD-L1 expression decreased in metastatic versus early TNBC, and with the impact of iatrogenic lymphodepletion over the course of the disease and treatment for it, immunotherapy benefit may be more pronounced in earlier settings (14, 15, 17, 25, 76) (Fig. 1). Initial studies of immunotherapy in early TNBC have been encouraging (Table 2), and results of further studies evaluating the role of immunotherapy in early breast cancer are highly anticipated.

Fig. 1
figure 1

Overview of potential biologic changes in TNBC over the natural history of the disease. The changes in iatrogenic lymphodepletion, TILs, and PD-L1 expression over the natural history of TNBC may impact the timing and effectiveness of immunotherapies. A trend towards decreased PD-L1 expression in metastatic versus early breast cancer has been seen, though a clear correlation has not been established. Epithelial-to-mesenchymal transition is being evaluated as a predictive marker for immunotherapy outcomes. TILs: tumor-infiltrating lymphocytes; PD-L1: programmed death-ligand 1; EMT: epithelial-mesenchymal transition. 1 Page et al. [27]. 2 Ogiya et al. [79]. 3 Manson et al., Tawfik et al. [86, 87]. 4 Terry et al. [88]