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Current Treatment Landscape and Emerging Therapies for Metastatic Triple-Negative Breast Cancer

Supplements and Featured PublicationsCombining Immune Checkpoint Inhibitors With Chemotherapy for the Treatment of Metastatic Triple-Negative Breast Cancer: An Overview for Managed Care Professionals
Volume 27
Issue 5


A lack of therapeutically targetable molecular alterations and its aggressive nature make triple-negative breast cancer (TNBC) a challenging disease. Chemotherapy is standard of care for most patients with metastatic disease, but median overall survival is less than 18 months. Unravelling the molecular underpinnings of TNBC revealed it to be a potentially highly immunogenic subtype within a more broadly immunologically inert cancer type, suggesting that it may respond to immunotherapy. An urgent need for new therapies is being filled in part by recent successes with immune checkpoint inhibitors (ICIs) targeting the programmed cell death receptor 1 and programmed death ligand 1 (PD-L1). Although single-agent ICIs had limited activity, exploration of rational combinations has yielded 2 new FDA approvals for atezolizumab and pembrolizumab in combination with chemotherapy, leading to a new standard of care for patients with PD-L1−positive disease. Two FDA-approved companion diagnostic PD-L1 assays are available to identify patients eligible for immunotherapy treatment, but other biomarkers of response are also being examined. Ongoing clinical trials are also evaluating a range of targeted therapies as combination partners, which may have immunomodulatory effects in addition to their main mechanism of action, complementing the activity of ICIs. This article will evaluate the current and emerging clinical trends in the use of ICIs as part of combination regimens in the treatment of patients with metastatic TNBC.

Am J Manag Care. 2021;27(suppl 5):S87-S96. https://doi.org/10.37765/ajmc.2021.88626


Worldwide, breast cancer is the most frequently diagnosed cancer in women. In the United States, it accounts for 30% of all cancers in women and is the second leading cause of cancer-related mortality, surpassed only by lung cancer. In 2021, an estimated 284,200 new cases of breast cancer and 44,130 deaths related to breast cancer will have occurred, representing 15% of all new cancer cases and 7.3% of all cancer deaths.1,2

Breast cancer is highly heterogeneous at the molecular level, characterized by the presence of discrete subtypes with distinct clinical behaviors. Several molecular biomarkers, including estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) expression have been incorporated into the breast cancer diagnostic staging system and impact therapy selection.3 Triple-negative breast cancer (TNBC) is a subgroup of breast cancer lacking expression of all three of these biomarkers; defined more specifically by the American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) as tumors that have less than 1% cellular expression of ER and PR, as determined by immunohistochemistry (IHC), and HER2 expression of 0 or 1+ by IHC or 2+ by IHC. An IHC result of 2+ is considered equivocal, which indicates the need to undergo a more accurate testing with fluorescence in situ hybridization; this will determine whether the tumor is HER2 positive or HER2 negative.4,5


Epidemiology and Prevalence

TNBCs account for approximately 15% to 20% of all newly diagnosed breast cancers. Incidence rates in non-Hispanic Black women are almost double the rates compared with other racial/ethnic groups, which may account for the fact that they experience 40% higher breast cancer-associated death rates.6,7

Breast cancer as a whole is most common in middle-aged and older women, with a median age at diagnosis of 62 years.8 There is a significant increase in incidence of breast cancer after the age of 40 and a bimodal age frequency distribution, with peaks near 45 and 65 years.9 By contrast, TNBC is more prevalent in younger women (<50 years), which presents a challenge as it often occurs in women who are not part of breast cancer screening programs, thus patients are diagnosed with more advanced stages of the disease. When it does occur in women undergoing regular screening, TNBC usually presents as an interval cancer (occurring between 2 mammograms).10

Along with younger age and Black race, a number of other risk factors associated with TNBC have been identified. These include the presence of a mutation in the breast cancer susceptibility genes, BRCA1 and BRCA2; up to 20% of patients with TNBC harbor a BRCA1/2 mutation.11 Notably, mutations in BRCA1/2 occur in approximately 2.5% of the Ashkenazi Jewish population, which puts them at high risk for developing TNBC.12 The penetrance of breast cancer at age 70 among BRCA1 mutation carriers in this population is 46% and for BRCA2 mutation carriers, it is 26%.13 Studies have also found that reproductive factors, including multiparity, young age at first pregnancy, and obesity are associated with an increased risk of TNBC, whereas breastfeeding may be associated with a reduced risk of TNBC.10,14-16

Prognosis and Pathogenesis

TNBC has historically been considered a single-disease entity, with diagnosis dependent on accurate assessment of the status of ER, PR, and HER2; “omics” technologies have revealed substantial complexity and heterogeneity at the molecular level. Breast cancers as a whole can be categorized into 4 major gene expression-based subtypes: luminal A (ER+, PR+, HER 2 -), luminal B (ER+, PR+, HER2+), HER2-enriched (ER-, PR-, HER2+), and basal-like (ER-, PR-, HER2-, CK5/6 and EGFR+).17-19 The majority of TNBCs fit into the basal-like subtype, but the remainder are distributed across the other subtypes.20 Meanwhile, studies have further elucidated at least 4 different gene expression-based TNBC subtypes: 2 basal subtypes (BL1 and BL2), a mesenchymal subtype (M), mesenchymal stem-like (MSL), immunomodulatory (IM) and a luminal androgen receptor (LAR) subtype.21 While these insights have yet to translate into clinical utility, they help to explain much of the variation in natural history and clinical behavior observed in TNBCs.

Most TNBCs are high-grade invasive ductal carcinomas with a high proliferative rate. Clinically, they are a particularly aggressive type of breast cancer, associated with poorer prognosis than other subtypes. TNBC accounts for approximately 5% of all cancer-related deaths annually22 and has one of the lowest 5-year relative survival rates, just 11.5% for patients with distant metastases.23 TNBC is a chemo-sensitive disease, with some of the highest pathologic complete response rates to neoadjuvant chemotherapy among breast cancer subtypes24; however, they have a higher rate of early recurrence and distant metastasis, particularly to the brain and lungs. Relapse rates peak between 3 and 5 years post-surgery and the risk of death following recurrence is higher in patients with TNBC compared with other types of breast cancer.10 The progress in understanding the heterogeneity of this disease has opened the door for new therapeutic strategies.

Metastatic TNBC (mTNBC)

Current Standard of Care

The lack of molecular targets in TNBC makes it challenging to treat and, in patients with locally recurrent inoperable or metastatic disease, chemotherapy remains the standard of care. No agent is specifically approved for TNBC, but chemotherapies that are approved for metastatic breast cancer are also used in the setting of TNBC. The National Comprehensive Cancer Network (NCCN) recommends either anthracyclines or taxanes as preferred first-line treatment options for patients who have not previously received these agents as neoadjuvant or adjuvant treatment.25 The NCCN guidelines detail the doses for preferred chemotherapy regimens. Patients with BRCA1/2 mutations can receive poly(ADP-ribose) polymerase (PARP) inhibitors or platinum-based (cisplatin or carboplatin) chemotherapy, based on the results of phase 3 clinical trials that demonstrated the efficacy of these agents, which exploit the DNA repair defects in tumors with BRCA1/2 mutations.25 The current guideline-recommended approach is single-agent chemotherapy, as combination chemotherapy has not been shown to prolong survival and is associated with an increased risk of toxicity. However, combination chemotherapy may be appropriate for patients with extensive disease or rapid progression of the disease with multiple organ involvement or who need rapid control of symptoms or disease.25

Second Line and Beyond

In patients who experience progression following first-line therapy, the recommended treatment strategy is for sequential use of other single-agent chemotherapy regimens, without treatment breaks, for as long as it is tolerated. Several options are available for later-line treatment in patients who have progressed and no longer tolerate chemotherapy.25 The trophoblast cell-surface antigen 2 (Trop-2)-targeted antibody-drug conjugate, sacituzumab govitecan, designed to provide targeted delivery of SN-38, the active metabolite of irinotecan, is approved in this setting.26,27 In patients with high levels of microsatellite instability (MSI), deficient mismatch repair (dMMR), or high tumor mutational burden (TMB), the PD-1-targeted immunotherapeutic agent pembrolizumab is approved as monotherapy.25 However, it should be noted that the tumor agnostic approval of pembrolizumab in patients with these biomarkers is based on clinical trials that did not include patients with TNBC.28,29 Figure 1 summarizes NCCN guideline-recommended standard of care for mTNBC.25

In a meta-analysis of phase 3 clinical trials of chemotherapy in the first-line setting for metastatic breast cancer, the pooled overall response rate (ORR) was 23% and median overall survival (OS) was 17.5 months. As patients progress, the efficacy of chemotherapy becomes even more limited, with a pooled ORR of 11% reported in a recent meta-analysis.30 Responses are generally short lived and chemotherapy is associated with toxicity that can impact patient quality of life; thus, there is an urgent need for new therapies to improve outcomes for patients with mTNBC.

The Evolving Immunotherapy Landscape

T cells, the cytotoxic effectors of the immune system, are able to recognize abnormal cellular antigens present on cancer cells and mount an antitumor immune response against them. In the absence of cancer, T-cell activation is closely regulated by multiple mechanisms, including signaling through inhibitory receptors, dubbed immune checkpoints, that prevent autoreactivity against the body’s own cells. Among the best-known immune checkpoints are programmed cell death PD-1 and its ligands PD-L1 and PD-L2. PD-1 is expressed on the surface of T cells, B cells, and natural killer cells, and interaction with its ligands, which are expressed on antigen-presenting cells, inhibits the T-cell response leading to loss of T-cell function. Cancer cells can modulate immune checkpoint signaling (PD-L1 is frequently expressed on tumor cells and immune cells in the tumor microenvironment, for example), thereby evading the immune system by downregulating T-cell cytotoxic activity.31

Immunotherapy, designed to reinvigorate the antitumor immune response, has been one of the major breakthroughs of the past decade in cancer research. Immune checkpoint inhibitors (ICIs), particularly monoclonal antibodies targeting PD-1 and PD-L1, are among the most successful types of immunotherapy, eliciting durable clinical responses across a range of solid tumor types. Despite their success, many patients do not benefit from ICI treatment, which has, in part, been attributed to differences in the immunogenicity of tumors. So-called “hot” tumors are characterized by infiltration of T cells into the tumor microenvironment, molecular signatures of immune activation, and increased PD-L1 expression levels, which has been shown to correlate with improved responses to ICIs.31-33

Historically, breast cancer has been considered a “cold” tumor; however, a better understanding of the molecular underpinnings of this disease has revealed that some subtypes are more immunogenic than others. TNBC presents a rational target for ICIs for a number of reasons, including its higher mutational load (meaning a greater number of neoantigens), increased number of tumor-infiltrating immune cells, and high PD-L1 expression levels. ICIs have been explored in numerous clinical trials in patients with mTNBC, but demonstrated limited single-agent activity. The focus has now shifted to exploring rational combination therapy in an effort to boost their effectiveness.34,35

Immunotherapy in Combination With Chemotherapy

Optimal combination strategies are designed to capitalize on additive or even synergistic activity between drugs with complementary mechanisms of action. In addition, with immunotherapy, combination regimens are also designed to exploit the potential immunomodulatory properties of the partner drug. The precise immunomodulatory properties of chemotherapy vary according to the specific agent but, in general, their cytotoxic activity causes tumor-associated antigens to be released into the circulation as cancer cells are destroyed, which can prime the antitumor immune response and boost responses to immunotherapy. In addition, chemotherapy specifically, the topoisomerase inhibitors, antimicrotubule agents, alkylating agents, and antimetabolites deplete immunosuppressive cells, such as regulatory T cells and myeloid-derived suppressor cells, making the tumor microenvironment more amenable to immunotherapy (Figure 236).37

A New Standard of Care: Atezolizumab plus nab-Paclitaxel

The combination of ICIs with chemotherapy in mTNBC has proved much more successful than single-agent ICIs and has yielded approval of 2 new treatment regimens by the FDA, shaping a new standard of care specifically in patients with PD-L1 expression. Following promising results from a phase 1 clinical trial,38 the combination of the PD-L1 inhibitor atezolizumab and nanoparticle albumin-bound paclitaxel (nab-paclitaxel) was evaluated in the randomized phase 3 IMpassion130 trial. Patients (N = 451) were randomized 1:1 to receive atezolizumab 840 mg intravenously (IV) on days 1 and 15 in combination with nab-paclitaxel 100 mg/m2 IV on days 1, 8, and 15 in 28-day cycles or placebo plus nab-paclitaxel. In an initial analysis, used to support FDA approval in 2019, the combination improved progression-free survival (PFS) compared with placebo plus chemotherapy in both the overall population (hazard ratio [HR], 0.80; 95% CI, 0.69-0.92; P = .002) and patients with PD-L1−positive tumors (defined as those with ≥1% PD-L1 expression on tumor-infiltrating immune cells as a percentage of tumor area) (HR, 0.62; 95% CI, 0.49-0.78; P <.001) (Table 135,39-47). Results from a second interim analysis were recently published; although median OS was numerically higher with the addition of atezolizumab, this did not cross the threshold for statistical significance (HR, 0.86; 95% CI, 0.72-1.02; P = .078). However, exploratory analyses suggested a significant improvement in OS in the PD-L1−positive population (HR, 0.71; 95% CI, 0.54-0.94). Grade 3/4 adverse effects (AEs) occurred in 49% of atezolizumab-treated patients compared with 43% of patients in the placebo group, most commonly neutropenia, peripheral neuropathy, decreased neutrophil count, and fatigue.39

The combination of atezolizumab and nab-paclitaxel is included in the NCCN guidelines as a category 1 preferred treatment option for the initial treatment of mTNBC in patients with PD-L1−positive disease, as determined by an FDA-approved companion diagnostic.25

Atezolizumab plus Paclitaxel

As nab-paclitaxel is not universally available, a randomized phase 3 trial was conducted to determine if paclitaxel could be used in its place in combination with atezolizumab in patients with previously untreated mTNBC (IMpassion131). A total of 651 patients were randomized 2:1 to receive atezolizumab 840 mg IV on days 1 and 15 plus paclitaxel 90 mg/m2 IV on days 1, 8, and 15 of 28-day cycles or placebo plus paclitaxel. Unexpectedly, using paclitaxel with atezolizumab did not improve PFS or OS in either the overall population or in patients with PD-L1−positive disease (Table 135,39-47). The reasons for this continue to be explored, but it has been suggested that increased use of steroid premedication to decrease the AEs of paclitaxel in IMpassion131 may have been partly to blame, by blunting the effects of atezolizumab.48 The FDA issued an alert to warn clinicians not to use paclitaxel in place of nab-paclitaxel in this setting.49 The ongoing randomized phase 3 IMpassion132 study (NCT03371017) is exploring the combination of atezolizumab with other types of chemotherapy (capecitabine or gemcitabine/carboplatin) for previously untreated mTNBC that recurs 12 months or less after completion of standard neoadjuvant chemotherapy.50

Pembrolizumab plus Chemotherapy

The PD-1 inhibitor pembrolizumab is also being tested in combination with chemotherapy in various ongoing clinical trials. In the randomized, phase 3 KEYNOTE-355 study, pembrolizumab in combination with chemotherapy (paclitaxel, nab-paclitaxel, or gemcitabine plus carboplatin) improved PFS compared with placebo plus chemotherapy (HR, 0.65; 95% CI, 0.49-0.86; P = .0012; Table 135,39-47) in the first-line treatment of patients with mTNBC, securing FDA approval for this combination in patients with PD-L1−positive disease defined as combined positive score (CPS) of greater than or equal to 10 in late 2020. In the trial, 847 patients were randomized 2:1 to receive pembrolizumab 200 mg IV every 3 weeks plus chemotherapy or placebo plus chemotherapy. The median PFS was 9.7 months with pembrolizumab-chemotherapy and 5.6 months with placebo-chemotherapy in patients with CPS of greater than or equal to 10. However, the median PFS was 7.6 and 5.6 months among patients with CPS of greater than or equal to 1, thus proving pembrolizumab treatment effect is increased with PD-L1 enrichment. The most common AEs included anemia (49% vs 46%), neutropenia (41% vs 38%), and nausea (39% vs 41%), and grade 3 and higher AEs occurred in 68% and 67% of patients, respectively. OS follow-up is ongoing.41 Additional data demonstrated that key secondary end points (ORR, duration of response, and disease control rate) also favored the pembrolizumab/chemotherapy combination and that the PFS benefit was observed regardless of the type of chemotherapy used.51 These data are currently utilized in the updated NCCN guidelines to reflect that this combination is a category 1 recommendation for patients who are eligible for immunotherapy treatments.

Another notable ongoing trial is the phase 1b/2 ENHANCE-1/KEYNOTE-150 study (NCT02513472), which is evaluating the combination of pembrolizumab and eribulin in patients with mTNBC previously treated with two or fewer systemic therapies. Patients were divided into PD-L1−positive and PD-L1−negative subgroups and by number of previous therapies; first-line setting (stratum 1, no prior therapy, N = 60) and second-line setting (stratum 2, 1-2 prior therapies, N = 89). No new safety signals were seen and treatment-emergent AEs were fatigue (66%), nausea (65%), peripheral sensory neuropathy (41%), alopecia (40%), and constipation (37%). Dose and schedule of eribulin was 1.4 mg/m2 IV on day 1 and day 8, dose and schedule of pembrolizumab was 200 mg as a flat dose IV on day 1, both in 21-day cycles.52

Nivolumab plus Chemotherapy

Based on preclinical research suggesting that there is immune modulatory properties for chemotherapy and irradiation, an adaptive, noncomparative phase 2 trial (TONIC study) was designed to look at this theory followed by nivolumab.53,54 Sixty-seven patients with mTNBC were randomized to receive nivolumab without induction or with 2-week low-dose induction, or with irradiation (3 × 8 Gy), or cyclophosphamide, or cisplatin or doxorubicin, all followed by nivolumab. The ORR in the full cohort was 20%. The majority of responses were observed in the cisplatin (ORR, 23%) and doxorubicin (ORR, 35%) cohorts. After doxorubicin and cisplatin induction, there was an upregulation of immune-related genes involved in PD-1−PD-L1 and T-cell cytotoxicity pathways. The clinical and translational data of this study indicate that short-term doxorubicin and cisplatin may induce a more favorable tumor microenvironment and increase the likelihood of response to PD-1 blockade in TNBC, supporting further trials addressing these combinations.46

Emerging Immunotherapy Combinations

Immunotherapy in Combination With Targeted Therapies

ICI-targeted therapy combinations are also emerging as potential strategies to improve response rates and potentially reduce toxicity in mTNBC, with several phase 1 and 2 trials reporting results (Table 135,39-47).

ICIs plus PARP Inhibitors

The BRCA1/2 genes encode proteins that are central to the repair of DNA double-strand breaks via the homologous recombination pathway of DNA repair. PARP enzymes are involved in the repair of single-strand breaks via base excision repair. BRCA1/2-deficient tumors become more heavily dependent on PARP-mediated pathways of repair, opening up a therapeutic vulnerability in breast cancers with homologous recombination deficiencies such as BRCA1/2 mutations.55 Several PARP inhibitors are approved for use in the approximately 15% of patients with mTNBC who harbor BRCA1/2 mutations.56 Studies have revealed that PARP inhibitors upregulate the expression of PD-L1 on tumor cells, and clinical trials are underway to explore potential synergy between PARP inhibitors and ICIs.57,58

In the open-label phase 1/2 TOPACIO/KEYNOTE-162 trial (NCT02657889), 55 patients with mTNBC were treated with niraparib 200 mg PO once daily and pembrolizumab 200 mg IV on day 1 of 21-day cycles. The combination demonstrated significant activity, especially among patients with BRCA1/2 mutations and appeared safe, with a tolerable safety profile. Grade 3 or higher AEs included anemia, thrombocytopenia, and fatigue.59 In the phase 1/2 MEDIOLA trial (NCT02734004), a combination of durvalumab (a PD-L1 inhibitor) and olaparib demonstrated significant activity and was well tolerated. Patients with various advanced solid tumors were treated with a 4-week run-in of olaparib 300 mg PO twice daily, followed by olaparib at the same dose in combination with durvalumab 1500 mg IV every 4 weeks until disease progression or unacceptable toxicity. The trial included 34 patients with metastatic, HER2-negative, germline BRCA1/2-mutated breast cancer; 30 were eligible for activity analysis showing a disease control at 12 weeks. Anemia and neutropenia were the most common AEs. Theseresults give further opportunities to study the combination of these agents in larger trials.44

ICIs plus PI3K/AKT Inhibitors

The PI3K/AKT pathway is one of the most frequently dysregulated in cancer and has emerged as a mechanism of resistance to a range of different cancer therapies, including ICIs.33 An ongoing phase 1b clinical trial (NCT03800836) is evaluating the triplet combination of AKT inhibitor ipatasertib (400 mg) PO on days 1-21, atezolizumab (840 mg) IV on days 1 and 15, and paclitaxel IV (80 mg/m2, arm A) or nab-paclitaxel IV (100 mg/m2, arm B) on days 1, 8, and 15 of 28-day cycles. Data for these 2 arms are outlined in Table 1.35,39-47 Two additional arms evaluated sequential regimens beginning with doublet therapy followed by the third agent on day 15 (ipatasertib plus paclitaxel adding in atezolizumab, arm C; atezolizumab plus paclitaxel adding in ipatasertib, arm D). In the overall population that included 114 patients, the ORR was 54% and median PFS was 7.2 months. There was no consistent trend in subgroup analyses according to PD-L1 expression or PI3K/AKT pathway alteration status.45 A phase 3 clinical trial of this combination has been initiated (NCT04177108).

Another notable ongoing clinical trial is the phase 2 MARIO-3 study, which is examining a triple combination of atezolizumab, nab-paclitaxel, and eganelisib, a PI3K gamma inhibitor. This combination was recently granted fast track designation by the FDA for the first-line treatment of advanced/mTNBC.60 Among 13 evaluable patients enrolled to date, 100% exhibited tumor reduction, regardless of PD-L1 status; ORR was 69.2% in the overall population and 100% in 5 PD-L1−positive patients.61,62

ICIs plus MEK Inhibitors

The mitogen-activated protein kinase (MAPK) pathway is frequently dysregulated in cancer, which prompted the development of small-molecule inhibitors of components of this pathway, such as MEK. In preclinical studies, MEK inhibitors have been shown to have immunomodulatory effects.63 In the phase 2 COLET trial, the MEK inhibitor cobimetinib was added to first-line paclitaxel for the treatment of patients with mTNBC but did not improve PFS.64 However, an exploratory biomarker analysis suggested that cobimetinib increased immune infiltration within the tumor microenvironment65 and, as such, a second part of the COLET trial began enrolling patients to be treated with a triplet of atezolizumab 840 mg IV on day 1 and 15, cobimetinib 60 mg PO on days 3-23, and paclitaxel IV 80 mg/m2 (cohort 2) or nab-paclitaxel IV 100 mg/m2 (cohort 3) on days 1, 8, and 15 of 28-day cycles. Data for 62 evaluable patients are presented in Table 1.35,39-47

Biomarkers for Immunotherapy Response

PD-L1 Expression

Another way to maximize patient outcomes with ICIs is to identify reliable predictive biomarkers to select patients most likely to benefit. Cancer cells and tumor-infiltrating immune cells have been shown to overexpress the PD-L1 protein, including 20% to 30% of patients with TNBC,66 and clinical trials have shown a correlation between higher levels of PD-L1 expression and efficacy of ICIs. Thus, the utility of PD-L1 as a potential predictive biomarker has been extensively studied.67-69

Both FDA-approved combination regimens in mTNBC are restricted to patients with PD-L1−positive tumors, and 2 antibody-based companion diagnostics for immunohistochemical analysis are available. The PD-L1 IHC 22C3 pharmDx (Dako North America) is approved for selecting patients for treatment with pembrolizumab, using a cutoff of CPS of 10 or greater. The Ventana PD-L1 (SP142) assay (Roche Diagnostics) is approved by the FDA for use with atezolizumab in mTNBC. In this case, the cutoff is an immune cell (IC) score of 1% or more. Figure 370andTable 270describe the scoring algorithms in more detail.

Although PD-L1 expression is currently the most important biomarker in clinical practice in TNBC, it faces numerous limitations. It does not reliably predict response, as some studies demonstrated responses in patients with PD-L1−negative tumors; thus, using these cutoffs may be missing patients who could benefit from ICIs. Other limitations include high levels of inter-observer variability, heterogeneity of PD-L1 expression within a tumor, differential PD-L1 expression level between the primary tumor and distant metastases, and variability in the antibodies and scoring systems used.24

Mismatch Repair Deficiencies

Mismatch repair (MMR) is an essential cellular mechanism of repair for DNA mismatches (alignment of 2 non-complementary bases), which can occur as a result of DNA damage, errors in DNA replication, or defects in other repair processes. Defects in MMR, which frequently occur in cancer cells due to mutations in the genes that govern DNA repair processes, cause DNA mismatches to go unrepaired, which can lead to the accumulation of mutations in the genome and drive the development of MSI—fluctuations in the length of repetitive sequences of DNA within the genome. dMMR or MSI-high tumors usually display many DNA mutations, which can serve as antigens that stimulate the immune system. Numerous studies have demonstrated that dMMR tumors are more responsive to ICIs, which resulted in the approval of pembrolizumab in patients with dMMR/MSI-high in both the refractory or metastatic solid tumors, the first approval of its kind for a tumor agnostic indication.68,71 The most commonly used methods to detect dMMR and MSI-high are to examine the expression of specific proteins involved in MMR by IHC or by DNA sequencing using polymerase chain reaction or next-generation sequencing (NGS). There are currently no specific FDA-approved assays, but a number of companies provide MSI-high/dMMR testing and companion diagnostics continue to be approved postmarketing.29,68

Tumor Mutation Burden (TMB)

TMB, defined as the number of mutations per megabase, has also emerged as a highly promising and clinically validated biomarker. Evaluating TMB allows assessment of the global spectrum of mutations across a given tumor and could provide a more comprehensive assessment of patients who might respond to ICIs than dMMR/MSI, which are just two of the many phenotypes that can cause hypermutable tumors. Studies have demonstrated that subsets of patients with high TMB exist across almost all cancer types and that assessing TMB through whole-exome sequencing or NGS can predict response to ICIs. Patients with high TMB experience improved outcomes following ICIs, it is thought as a result of the production of a greater number of antigenic peptides that provoke an antitumor immune response.68,72 The FDA recently approved pembrolizumab for use across cancers with high TMB (defined as having at least 10 mutations/Mb), marking the first approval using this biomarker and another tumor agnostic indication for pembrolizumab. Foundation Medicine’s FoundationOne CDx assay was approved as a companion diagnostic.68,72


The development of novel treatments for mTNBC remains a significant unmet need. ICIs are a promising new option for patients with PD-L1−positive disease and are already shaping a new standard of care in combination with chemotherapy. With a number of ongoing studies reporting promising preliminary data for other ICI-chemotherapy and ICI-targeted therapy combination strategies, the stage is set for the treatment of mTNBC to further evolve over the next few years. Although PD-L1 expression is an established biomarker to select patients for treatment with ICIs, there are limitations to its use and there is a need to investigate additional biomarkers to predict response. In better understanding new and emerging treatment options and challenges and concerns regarding their use, managed care professionals can help to ensure optimal outcomes for patients with this challenging tumor type.

The FDA is holding a public meeting of the Oncologic Drugs Advisory Committee (ODAC) on April 27-29 to discuss multiple indications from different drugs granted accelerated approval that have since reported results from a confirmatory trial that have not verified clinical benefit.One of the indications listed on the agenda for discussion is atezolizumab in combination with nab-paclitaxel for the treatment of adult patients with unresectable locally advanced or metastatic triple-negative breast cancer whose tumors express PD-L1.73

Author affiliation: Nelly G. Adel, PharmD, BCOP, BCPS, is the chair of Pharmacy Practice and associate professor, oncology, Touro College of Pharmacy, New York, NY.

Funding source: This activity is supported by an educational grant from Merck Sharp & Dohme Corp.

Author disclosure: Dr Adel has no relevant financial relationships with commercial interests to disclose.

Author information: Critical revision of the manuscript for important intellectual content; provision of study materials; supervision; final approval of manuscript.

Address correspondence to: nelly.adel@touro.edu

Medical writing and editorial support provided by: Jane de Lartigue, PhD


1. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68(6):394-424. doi: 10.3322/caac.21492

2. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2021. CA Cancer J Clin. 2021;71:7-33.
doi: 10.3322/caac.21654

3. Giuliano AE, Connolly JL, Edge SB, et al. Breast cancer—major changes in the American Joint Committee on Cancer eighth edition cancer staging manual. CA Cancer J Clin. 2017;67(4):290-303. doi: 10.3322/caac.21393

4. Wolff AC, Hammond ME, Allison KH, et al. Human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists clinical practice guideline focused update. J Clin Oncol. 2018;36(20):2105-2122. doi: 10.1200/JCO.2018.77.8738

5. Allison KH, Hammond ME, Dowsett M, et al. Estrogen and progesterone receptor testing in breast cancer: ASCO/CAP guideline update. J Clin Oncol. 2020;38(12):1346-1366. doi: 10.1200/JCO.19.02309

6. DeSantis CE, Miller KD, Goding Sauer A, Jemal A, Siegel RL. Cancer statistics for African Americans, 2019. CA Cancer J Clin. 2019;69(3):211-233. doi: 10.3322/caac.21555

7. DeSantis CE, Ma J, Gaudet MM, et al. Breast cancer statistics, 2019. CA Cancer J Clin. 2019;69(6):438-451. doi: 10.3322/caac.21583

8. Surveillance, Epidemiology, and End Results Program. Female breast cancer—cancer stat facts. Accessed January 1, 2021. seer.cancer.gov/statfacts/html/breast.html

9. Allott EH, Shan Y, Chen M, et al. Bimodal age distribution at diagnosis in breast cancer persists across molecular and genomic classifications. Breast Cancer Res Treat. 2020;179(1):185-195. doi: 10.1007/s10549-019-05442-2

10. Kumar P, Aggarwal R. An overview of triple-negative breast cancer. Arch Gynecol Obstet. 2016;293(2):247-269. doi: 10.1007/s00404-015-3859-y

11. Gonzalez-Angulo AM, Timms KM, Liu S, et al. Incidence and outcome of BRCA mutations in unselected patients with triple receptor-negative breast cancer. Clin Cancer Res. 2011;17(5):1082-1089. doi: 10.1158/1078-0432.CCR-10-2560

12. Metcalfe KA, Eisen A, Lerner-Ellis J, Narod SA. Is it time to offer BRCA1 and BRCA2 testing to all Jewish women? Curr Oncol. 2015;22(4):e233-e236. doi: 10.3737/co.22.2527

13. Satagopan JM, Offit K, Foulkes W, et al. The lifetime risks of breast cancer in Ashkenazi Jewish carriers of BRCA1 and BRCA2 mutations. Cancer Epidemiol Biomarkers Prev. 2001;10(5):467-473.

14. Phipps AI, Chlebowski RT, Prentice R, et al. Body size, physical activity, and risk of triple-negative and estrogen receptor-positive breast cancer. Cancer Epidemiol Biomarkers Prev. 2011;20(3):454-463. doi: 10.1158/1055-9965.EPI-10-0974

15. Phipps AI, Chlebowski RT, Prentice R, et al. Reproductive history and oral contraceptive use in relation to risk of triple-negative breast cancer. J Natl Cancer Inst. 2011;103(6):470-477. doi: 10.1093/jnci/djr030

16. John EM, Hines LM, Phipps AI, et al. Reproductive history, breast-feeding and risk of triple negative breast cancer: The Breast Cancer Etiology in Minorities (BEM) study. Int J Cancer. 2018;142(11):2273-2285. doi: 10.1002/ijc.31258

17. Perou CM, Sørlie T, Eisen MB, et al. Molecular portraits of human breast tumours. Nature. 2000;406(6797):747-752. doi: 10.1038/35021093

18. Sørlie T, Perou CM, Tibshirani R, et al. Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci U S A. 2001;98(19):10869-10874. doi: 10.1073/pnas.191367098

19. Cancer Genome Atlas Network. Comprehensive molecular portraits of human breast tumours. Nature. 2012;490(7418):61-70. doi: 10.1038/nature11412

20. Marra A, Trapani D, Viale G, Criscitiello C, Curigliano G. Practical classification of triple-negative breast cancer: intratumoral heterogeneity, mechanisms of drug resistance, and novel therapies. NPJ Breast Cancer. 2020;6:54. doi: 10.1038/s41523-020-00197-2

21. Lehmann BD, Bauer JA, Chen X, et al. Identification of human triple-negative breast cancer subtypes
and preclinical models for selection of targeted therapies. J Clin Invest. 2011;121(7):2750-2767. doi: 10.1172/JCI45014

22. Won KA, Spruck C. Triple‑negative breast cancer therapy: current and future perspectives. Int J Oncol. 2020;57(6):1245-1261. doi: 10.3892/ijo.2020.5135

23. Surveillance, Epidemiology, and End Results Program. Female breast cancer subtypes—cancer stat facts. Accessed January 7, 2021. seer.cancer.gov/statfacts/html/breast-subtypes.html

24. Michel LL, von Au A, Mavratzas A, Smetanay K, Schütz F, Schneeweiss A. Immune checkpoint blockade in patients with triple-negative breast cancer. Target Oncol. 2020;15(4):415-428. doi: 10.1007/s11523-020-00730-0

25. National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology (NCCN Guidelines). Breast Cancer. Version 2.2021. Accessed March 15, 2021. www.nccn.org/professionals/physician_gls/pdf/breast.pdf

26. Bardia A, Mayer IA, Vahdat LT, et al. Sacituzumab govitecan-hziy in refractory metastatic triple-negative breast cancer. N Engl J Med. 2019;380(8):741-751. doi: 10.1056/NEJMoa1814213

27. Syed YY. Sacituzumab govitecan: first approval. Drugs. 2020;80(10):1019-1025. doi: 10.1007/s40265-020-01337-5

28. Marabelle A, Fakih M, Lopez J, et al. Association of tumour mutational burden with outcomes in patients with advanced solid tumours treated with pembrolizumab: prospective biomarker analysis
of the multicohort, open-label, phase 2 KEYNOTE-158 study. Lancet Oncol. 2020;21(10):1353-1365. doi: 10.1016/S1470-2045(20)30445-9

29. Marcus L, Lemery SJ, Keegan P, Pazdur R. FDA approval summary: pembrolizumab for the treatment of microsatellite instability-high solid tumors. Clin Cancer Res. 2019;25(13):3753-3758. doi: 10.1158/1078-0432.CCR-18-4070

30. Li CH, Karantza V, Aktan G, Lala M. Current treatment landscape for patients with locally recurrent inoperable or metastatic triple-negative breast cancer: a systematic literature review. Breast Cancer Res. 2019;21(1):143. doi: 10.1186/s13058-019-1210-4

31. Hargadon KM, Johnson CE, Williams CJ. Immune checkpoint blockade therapy for cancer: an overview of FDA-approved immune checkpoint inhibitors. Int Immunopharmacol. 2018;62:29-39. doi: 10.1016/j.intimp.2018.06.001

32. Duan Q, Zhang H, Zheng J, Zhang L. Turning cold into hot: firing up the tumor microenvironment. Trends Cancer. 2020;6(7):605-618. doi: 10.1016/j.trecan.2020.02.022

33. Fujiwara Y, Mittra A, Naqash AR, Takebe N. A review of mechanisms of resistance to immune checkpoint inhibitors and potential strategies for therapy. Cancer Drug Resist. 2020;3(3):252-275. doi: 10.20517/cdr.2020.11

34. Simmons CE, Brezden-Masley C, McCarthy J, McLeod D, Joy AA. Positive progress: current and evolving role of immune checkpoint inhibitors in metastatic triple-negative breast cancer. Ther Adv Med Oncol. 2020;12:1-15. doi: 10.1177/1758835920909091

35. Keenan TE, Tolaney SM. Role of immunotherapy in triple-negative breast cancer. J Natl Compr Canc Netw. 2020;18(4):479-489. doi: 10.6004/jnccn.2020.7554

36. Heinhuis KM, Ros W, Kok M, Steeghs N, Beijnen JH, Schellens JH. Enhancing antitumor response by combining immune checkpoint inhibitors with chemotherapy in solid tumors. Ann Oncol. 2019;30(2):219-235. doi: 10.1093/annonc/mdy551

37. Murciano-Goroff YR, Warner AB, Wolchok JD. The future of cancer immunotherapy: microenvironment-targeting combinations. Cell Res. 2020;30(6):507-519. doi: 10.1038/s41422-020-0337-2

38. Adams S, Diamond JR, Hamilton E, et al. Atezolizumab plus nab-paclitaxel in the treatment of metastatic triple-negative breast cancer with 2-year survival follow-up: a phase 1b clinical trial. JAMA Oncol. 2019;5(3):334-342. doi: 10.1001/jamaoncol.2018.5152

39. Schmid P, Rugo HS, Adams S, et al; IMpassion130 Trial Investigators. Atezolizumab plus nab-paclitaxel as first-line treatment for unresectable, locally advanced or metastatic triple-negative breast cancer (IMpassion130): updated efficacy results from a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2020;21(1):44-59. doi: 10.1016/S1470-2045(19)30689-8

40. Miles DW, Gligorov J, André F, et al. Primary results from IMpassion131, a double-blind placebo-controlled randomised phase III trial of first-line paclitaxel (PAC) ± atezolizumab (atezo) for unresectable locally advanced/metastatic triple-negative breast cancer (mTNBC). Ann Oncol. 2020;31:S1142-S1215. doi: 10.1016/j.annonc.2020.08.2243

41. Cortes J, Cescon DW, Rugo HS, et al; KEYNOTE-355 Investigators. Pembrolizumab plus chemotherapy versus placebo plus chemotherapy for previously untreated locally recurrent inoperable or metastatic triple-negative breast cancer (KEYNOTE-355): a randomised, placebo-controlled, double-blind, phase 3 clinical trial. Lancet. 2020;396(10265):1817-1828. doi: 10.1016/S0140-6736(20)32531-9

42. Tolaney SM, Barroso-Sousa R, Keenan T, et al. Effect of eribulin with or without pembrolizumab on progression-free survival for patients with hormone receptor-positive, ERBB2-negative metastatic breast cancer: a randomized clinical trial. JAMA Oncol. 2020;6(10):1598-1605. doi: 10.1001/jamaoncol.2020.3524

43. Brufsky A, Kim SB, Zvirbule Z, et al. Phase II COLET study: Atezolizumab (A) + cobimetinib (C) + paclitaxel (P)/nab-paclitaxel (nP) as first-line (1L) treatment (tx) for patients (pts) with locally advanced or metastatic triple-negative breast cancer (mTNBC). J Clin Oncol. 2019;37(suppl 15):1013-1013. doi: 10.1200/JCO.2019.37.15_suppl.1013

44. Domchek SM, Postel-Vinay S, Im SA, et al. Olaparib and durvalumab in patients with germline BRCA-mutated metastatic breast cancer (MEDIOLA): an open-label, multicentre, phase 1/2, basket study. Lancet Oncol. 2020;21(9):1155-1164. doi: 10.1016/S1470-2045(20)30324-7

45. Schmid P, Savas P, Espinosa E, et al. Phase 1b study evaluating a triplet combination of ipatasertib (IPAT), atezolizumab, and a taxane as first-line therapy for locally advanced/metastatic triple-negative breast cancer (TNBC). Presented at the (virtual) San Antonio Breast Cancer Symposium. December 9, 2020. Abstract PS12-28.

46. Voorwerk L, Slagter M, Horlings HM, et al. Immune induction strategies in metastatic triple-negative breast cancer to enhance the sensitivity to PD-1 blockade: the TONIC trial. Nat Med. 2019;25(6):920-928. doi: 10.1038/s41591-019-0432-4

47. Schmid P, Adams S, Rugo HS, et al; IMpassion130 Trial Investigators. Atezolizumab and nab-paclitaxel in advanced triple-negative breast cancer. N Engl J Med. 2018;379(22):2108-2121. doi: 10.1056/NEJMoa1809615

48. Helwick C. IMpassion131: No benefit for atezolizumab plus paclitaxel in triple-negative breast cancer. The ASCO Post. October 10, 2020. Accessed January 8, 2021. ascopost.com/issues/october-10-2020/impassion131-no-benefit-for-atezolizumab-plus-paclitaxel-in-triple-negative-breast-cancer/

49. FDA issues alert about efficacy and potential safety concerns with atezolizumab in combination with paclitaxel for treatment of breast cancer. FDA. Published September 8, 2020. Accessed January 6, 2021. www.fda.gov/drugs/resources-information-approved-drugs/fda-issues-alert-about-efficacy-and-potential-safety-concerns-atezolizumab-combination-paclitaxel

50. Cortés J, André F, Gonçalves A, et al. IMpassion132 Phase III trial: atezolizumab and chemotherapy in early relapsing metastatic triple-negative breast cancer. Future Oncol. 2019;15(17):1951-1961. doi:10.2217/fon-2019-0059

51. Rugo HS, Schmid P, Cescon DW, et al. Additional efficacy endpoints from the phase 3 KEYNOTE-355 study of pembrolizumab plus chemotherapy vs placebo plus chemotherapy as first-line therapy for locally recurrent inoperable or metastatic triple-negative breast cancer. Presented at the (virtual) San Antonio Breast Cancer Symposium. December 10, 2020. Abstract GS3-01.

52. Tolaney SM, Kalinsky K, Kaklamani VG, et al. A phase Ib/II study of eribulin (ERI) plus pembrolizumab (PEMBRO) in metastatic triple-negative breast cancer (mTNBC) (ENHANCE 1). J Clin Oncol. 2020;38(suppl 15):1015. doi: 10.1200/JCO.2020.38.15_suppl.1015

53. Scurr, M. et al. Low-dose cyclophosphamide induces antitumor T-cell responses, which associate with survival in metastatic colorectal cancer. Clin Cancer Res. 2017; 23(22), 6771–6780. doi: 10.1158/1078-0432.CCR-17-0895

54. de Biasi AR Villena-Vargas J, Adusumilli PS. Cisplatin-induced antitumor immunomodulation: a review of preclinical and clinical evidence. Clin Cancer Res. 2014; 20(21), 5384–5391. doi: 10.1158/1078-0432.CCR-14-1298

55. Li H, Liu ZY, Wu N, Chen YC, Cheng Q, Wang J. PARP inhibitor resistance: the underlying mechanisms and clinical implications. Mol Cancer. 2020;19(1):107. doi: 10.1186/s12943-020-01227-0

56. Couch FJ, Hart SN, Sharma P, et al. Inherited mutations in 17 breast cancer susceptibility genes among a large triple-negative breast cancer cohort unselected for family history of breast cancer. J Clin Oncol. 2015;33(4):304-311. doi: 10.1200/JCO.2014.57.1414

57. Jiao S, Xia W, Yamaguchi H, et al. PARP inhibitor upregulates PD-L1 expression and enhances cancer-associated immunosuppression. Clin Cancer Res. 2017;23(14):3711-3720. doi: 10.1158/1078-0432.CCR-16-3215

58. Pantelidou C, Sonzogni O, De Oliveria Taveira M, et al. PARP inhibitor efficacy depends on CD8+ T-cell recruitment via intratumoral STING pathway activation in BRCA-deficient models of triple-negative breast cancer. Cancer Discov. 2019;9(6):722-737. doi: 10.1158/2159-8290.CD-18-1218

59. Vinayak S, Tolaney SM, Schwartzberg L, et al. Open-label clinical trial of niraparib combined with pembrolizumab for treatment of advanced or metastatic triple-negative breast cancer. JAMA Oncol. 2019;5(8):1132-1140. doi: 10.1001/jamaoncol.2019.1029

60. Infinity receives fast track designation for eganelisib in combination with a checkpoint inhibitor and chemotherapy for first-line treatment of advanced TNBC. News release. Infinity Pharmaceuticals. September 29, 2020. Accessed January 6, 2021. investors.infi.com/news-releases/news-release-details/infinity-receives-fast-track-designation-eganelisib-combination

61. Hamilton E, Lee A, Swart R, et al. Mario-3 phase II study safety run-in evaluating a novel triplet combination of eganelisib (formerly IPI-549), atezolizumab (atezo), and nab-paclitaxel (nab-pac) as first-line (1L) therapy for locally advanced or metastatic triple-negative breast cancer (TNBC). Presented at the (virtual) San Antonio Breast Cancer Symposium. December 9, 2020. Abstract PS11-32.

62. Infinity Pharmaceuticals. Eganelisib: first-in-class PI3K-γ inhibitor targeting immune suppressive myeloid cells in metastatic triple-negative breast cancer. December 9, 2020. Accessed January 22, 2021. investors.infi.com/static-files/c2eb7c11-124e-46ec-9faa-6e3ae2adf090

63. Loi S, Dushyanthen S, Beavis PA, et al. RAS/MAPK activation is associated with reduced tumor-infiltrating lymphocytes in triple-negative breast cancer: therapeutic cooperation between MEK and PD-1/PD-L1 immune checkpoint inhibitors. Clin Cancer Res. 2016;22(6):1499-1509. doi: 10.1158/1078-0432.CCR-15-1125

64. Brufsky A, Miles D, Zvirbule Z, et al. Abstract P5-21-01: Cobimetinib combined with paclitaxel as first-line treatment for patients with advanced triple-negative breast cancer (COLET study): primary analysis of cohort I. Cancer Res. 2018;78(suppl 4):P5-P5-21-01. doi: 10.1158/1538-7445.SABCS17-P5-21-01

65. Wongchenko M, Miles D, Kim SB, et al. Exploratory biomarker analysis of first-line cobimetinib (C) + paclitaxel (P) in patients (pts) with advanced triple-negative breast cancer (TNBC) from the phase 2 COLET study. Eur J Cancer. 2016;69:S148-S149. doi: 10.1016/S0959-8049(16)33041-6

66. Ali HR, Glont SE, Blows FM, et al. PD-L1 protein expression in breast cancer is rare, enriched in basal-like tumours and associated with infiltrating lymphocytes. Ann Oncol. 2015;26(7):1488-1493. doi: 10.1093/annonc/mdv192

67. Sunshine J, Taube JM. PD-1/PD-L1 inhibitors. Curr Opin Pharmacol. 2015;23:32-38. doi: 10.1016/j.coph.2015.05.011

68. Arora S, Velichinskii R, Lesh RW, et al. Existing and emerging biomarkers for immune checkpoint immunotherapy in solid tumors. Adv Ther. 2019;36(10):2638-2678. doi: 10.1007/s12325-019-01051-z

69. Ganesan S, Mehnert J. Biomarkers for response to immune checkpoint blockade. Ann Rev Cancer Biol. 2020;4(1):331-351. doi: 10.1146/annurev-cancerbio-030419-033604

70. Eckstein M, Cimadamore A, Hartmann A, et al. PD-L1 assessment in urothelial carcinoma: a practical approach. Ann Transl Med. 2019;7(22):690. doi: 10.21037/atm.2019.10.24

71. Zhao P, Li L, Jiang X, Li Q. Mismatch repair deficiency/microsatellite instability-high as a predictor for anti-PD-1/PD-L1 immunotherapy efficacy. J Hematol Oncol. 2019;12(1):54. doi: 10.1186/s13045-019-0738-1

72. Klempner SJ, Fabrizio D, Bane S, et al. Tumor mutational burden as a predictive biomarker for response to immune checkpoint inhibitors: a review of current evidence. Oncologist. 2020;25(1):e147-e159. doi: 10.1634/theoncologist.2019-0244

73. April 27-29, 2021: Meeting of the Oncologic Drugs Advisory Committee Meeting Announcement. US FDA. Updated March 12, 2021. Accessed March 26, 2021. www.fda.gov/advisory-committees/advisory-committee-calendar/april-27-29-2021-meeting-oncologic-drugs-advisory-committee-meeting-announcement-04272021-04292021

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