ER/PR negative, HER2-negative (triple-negative) breast cancer

INTRODUCTION — Triple-negative breast cancer (TNBC) is a term that has historically been applied to cancers that lack expression of the estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). TNBC tends to behave more aggressively than other types of breast cancer. Unlike other breast cancer subtypes (ie, ER-positive, HER2-positive subtypes), there are no approved targeted treatments available, although immunotherapy (in combination with chemotherapy) is available for those with advanced TNBC that expresses programmed cell death ligand 1 (PD-L1). For purposes of this review, we consider "triple-negative" to mean cancers that have <1 percent expression of ER and PR as determined by immunohistochemistry (IHC), and that are, for HER2, either 0 to 1+ by IHC, or IHC 2+ and fluorescence in situ hybridization (FISH) negative (not amplified), according to American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) guidelines [1-3]. Although the basic principles of diagnosis and management of TNBC are similar to those of breast cancer in general, many aspects, including risk factors, molecular and pathologic characteristics, natural history, and chemotherapy sensitivity, are unique to TNBC and will be reviewed here.

A more extensive discussion on surgical management, neoadjuvant chemotherapy, adjuvant chemotherapy of non-metastatic breast cancer, and the treatment of metastatic breast cancer is covered separately.

●(See "Overview of the treatment of newly diagnosed, invasive, non-metastatic breast cancer".)

●(See "Overview of the approach to metastatic breast cancer".)

EPIDEMIOLOGY — TNBC accounts for approximately 15 percent of breast cancers diagnosed worldwide, which amounts to almost 200,000 cases each year [4]. Compared with hormone receptor-positive breast cancer, TNBC is more commonly diagnosed in women younger than 40 years. In one study, there was a twofold higher attributable risk of TNBC in women under 40 years compared with women over 50 years (odds ratio [OR] 2.13, 95% CI 1.34-3.39) [5]. In addition, TNBC appears to be relatively more common among Black women compared with White women (OR 2.41, 95% CI 1.81-3.21) [5].

Risk factors associated with the diagnosis of TNBC include:

●Positive BRCA mutation status – Up to 20 percent of patients with TNBC harbor a breast cancer susceptibility gene (BRCA) mutation, particularly in BRCA1 [6]. By contrast, less than 6 percent of all breast cancers are associated with a BRCA mutation. Given this finding, any patient with triple-negative disease should be offered a referral to a genetic counselor to discuss BRCA germline testing [7]. Moreover, any patient age 60 years or younger with TNBC should undergo BRCA germline testing.

●Race/ethnicity – Several population-based studies have found that African American women have a higher risk of TNBC compared with White women [8,9]. However, African American women can certainly have ER-positive and/or HER2-positive disease, and testing their tumors for these markers is essential.

●Premenopausal status – Premenopausal status has been associated with increased incidence of TNBC diagnosis as compared with postmenopausal status [8,10]. As with African American women, premenopausal women can frequently have ER-positive and/or HER2-positive disease, and testing their tumors for these markers is essential.

●Other factors – Studies have suggested relationships between other factors such as obesity and a young age of first pregnancy with an increased risk of TNBC, while breastfeeding and parity may be associated with lower risks [5,8,11-13]. However, these factors are less well validated and rarely factor into clinical considerations.

CLINICAL PRESENTATION — TNBCs present with rapid growth, and are more likely to be diagnosed clinically rather than mammographically than ER-positive cancers [14] or as interval cancers between mammograms [15]. However, intrinsic differences in the density of breast tissue among women diagnosed with TNBC may also explain these differences in presentation. (See "Clinical features, diagnosis, and staging of newly diagnosed breast cancer", section on 'Clinical features'.)

PATHOLOGIC CHARACTERISTICS — TNBC is usually high grade, and the most common histology is infiltrating ductal carcinoma [16], although a rare histologic subtype, medullary carcinoma, is generally triple negative. TNBCs can exhibit geographic necrosis, a pushing border of invasion, and a stromal lymphocytic response (table 1) [16]. (See "Pathology of breast cancer".)

An uncommon subgroup of TNBCs is defined histopathologically as metaplastic. However, this is a diverse group of cancer types ranging from squamous to stromal in nature. These cancers are discussed in more detail separately. (See "Pathology of breast cancer", section on 'Metaplastic carcinoma'.)

By definition, TNBC lacks immunohistochemical (IHC) expression of the ER, PR, and HER2. Cut-offs used for ER, PR, and HER2 to make this diagnosis are discussed below. (See 'Diagnosis and staging' below.)

Since these three biomarkers represent the only known approved targets for breast cancer treatment, considerable effort has been made to better understand other biologic forces driving TNBC.

Molecular classification of TNBC — The triple-negative clinical phenotype mostly comprises the basal-like molecular subtype, although triple-negative and basal breast cancers are not synonymous and there is substantial heterogeneity within TNBCs.

As examples, in one study of utilizing DNA and RNA profiling of TNBCs, four stable subtypes were identified: luminal androgen receptor, mesenchymal, basal-like immunosuppressed, and basal-like immune-activated [17]. In another study, 172 triple-negative tumors based on IHC staining were correlated with gene expression profiles that defined the basal subtype [18]. Only 71 percent of TNBCs were assigned the basal subtype. In a converse analysis (where subtype was identified and correlated with IHC staining) of 160 tumors, 77 percent of basal tumors were triple negative by IHC. Other evidence from copy number variation and mutational analyses has also suggested wide variability and breadth of clonal spectra in TNBC [19].

Basal breast cancer is characterized by the genomic expression of the "basal cluster," a unique cluster of genes that includes the epidermal growth factor receptor (EGFR, also called HER1), basal cytokeratins 5/6, c-Kit, the proliferation cluster, and low expression of the hormone receptor- and HER2-related genes [16,20-22]. Separate subtypes of TNBC have been characterized by gene expression, including two basal-like subtypes (BL1 and BL2), as well as immunomodulatory, mesenchymal, mesenchymal stem-like, and luminal androgen subtypes [23]. Additional subtypes that have been characterized include claudin-low and interferon-rich subtypes [24,25]. The different subtypes of TNBCs are covered separately. (See "Prognostic and predictive factors in early, non-metastatic breast cancer".)

Gene expression analysis has also revealed that the tumor suppressor gene p53 (TP53) and several DNA repair genes, particularly the breast cancer susceptibility genes (BRCA), are either mutated or aberrantly expressed in TNBC. These molecular features may have implications for chemotherapy sensitivity to platinum and other directly DNA-damaging agents [26,27]. (See 'Metastatic disease' below.)

Taken together, these studies have produced mixed results with varying conclusions among the different investigators. None has reached the level of providing clinical considerations at present.

DIAGNOSIS AND STAGING

●Diagnosis – We consider "triple-negative" to mean cancers that have <1 percent expression of ER and PR as determined by immunohistochemistry (IHC), and that are either 0 to 1+ by IHC, or IHC 2+ and fluorescence in situ hybridization (FISH)-negative (not amplified), according to American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) guidelines [1-3]. (See "Hormone receptors in breast cancer: Clinical utility and guideline recommendations to improve test accuracy" and "HER2 and predicting response to therapy in breast cancer", section on 'Testing for HER2 expression'.)

Receptor testing and the cut-offs used to determine ER, PR, and HER2 statuses were developed to determine the odds of response to endocrine and HER2-directed therapy, respectively. They were not developed to distinguish a distinct biologic subtype of breast cancer, such as the "triple-negative" phenotype. (See "Prognostic and predictive factors in early, non-metastatic breast cancer", section on 'Receptor status' and "Prognostic and predictive factors in metastatic breast cancer", section on 'Tests done on metastatic tissue'.)

In support of this definition of ER and PR receptor-negative status, an analysis of cooperative group studies with centrally determined ER, PR, and molecular subtype suggests that this group is molecularly heterogeneous, including both luminal and nonluminal subtypes [28,29]. (See "Hormone receptors in breast cancer: Clinical utility and guideline recommendations to improve test accuracy", section on 'Assays for ER and PR' and "HER2 and predicting response to therapy in breast cancer", section on 'Testing for HER2 expression'.)

●Staging – The indications for radiographic staging in breast cancer, as well as appropriate imaging modalities, are discussed elsewhere. (See "Clinical features, diagnosis, and staging of newly diagnosed breast cancer", section on 'Postdiagnosis evaluation' and "Clinical features, diagnosis, and staging of newly diagnosed breast cancer", section on 'Staging'.)

The clinical staging of breast cancer is identical across breast cancer subtypes using the American Joint Committee on Cancer and the International Union for Cancer Control (AJCC-UICC) Tumor, Node, Metastasis (TNM) breast cancer staging system (table 2 and table 3 and table 4). (See "Clinical features, diagnosis, and staging of newly diagnosed breast cancer", section on 'Staging'.)

GENETICS EVALUATION

BRCA testing — In light of the association of particular breast cancer susceptibility gene 1 (BRCA1) mutations with TNBC, we recommend that women diagnosed at 60 years or younger with a localized TNBC, or those of any age with metastatic TNBC, undergo BRCA mutation testing regardless of family history. (See "Genetic testing and management of individuals at risk of hereditary breast and ovarian cancer syndromes".)

For those with metastatic disease, results of BRCA testing have therapeutic implications. (See 'Metastatic disease' below.)

NON-METASTATIC DISEASE — The neoadjuvant or adjuvant chemotherapy options for patients with TNBC are similar to the approaches used in other breast cancer phenotypes. The principles for the surgical management of and radiation therapy options for breast cancer are also applied in a similar way across breast cancer subtypes. (See "Breast-conserving therapy" and "The role of local therapies in metastatic breast cancer" and "Adjuvant radiation therapy for women with newly diagnosed, non-metastatic breast cancer" and "Radiation therapy techniques for newly diagnosed, non-metastatic breast cancer".)

Tumors >0.5 cm

Chemotherapy — Chemotherapy is recommended for women with TNBC >0.5 cm or with node-positive TNBC (regardless of tumor size). These patients have a higher risk of relapse compared with other breast cancer phenotypes and are not candidates for other forms of targeted therapy (ie, HER2-directed treatment or endocrine therapy).

Neoadjuvant versus adjuvant administration — Neoadjuvant chemotherapy (NACT) is the preferable approach in patients with locally advanced breast cancer or for those who are not candidates for or unlikely to have a good cosmetic outcome with breast conservation. For patients receiving NACT, pathologic complete response is associated with improvement in disease-free survival (DFS) [30-32]. Additionally, patients with smaller (eg, T1c) TNBCs may be offered neoadjuvant therapy, particularly if they might be candidates for additional treatments in the adjuvant setting if residual disease is identified. The approach to neoadjuvant therapy for patients with breast cancer, including further discussion of appropriate candidates, with special considerations for those with TNBC, is found elsewhere. (See "General principles of neoadjuvant management of breast cancer" and "General principles of neoadjuvant management of breast cancer", section on 'Patient selection' and "Choice of neoadjuvant chemotherapy for HER2-negative breast cancer", section on 'Special considerations for triple-negative disease'.)

The role for additional chemotherapy in the adjuvant setting for women with residual cancer after neoadjuvant chemotherapy is discussed elsewhere. (See "Selection and administration of adjuvant chemotherapy for HER2-negative breast cancer", section on 'Patients who received neoadjuvant treatment'.)

Benefits — Stage for stage, there is a larger absolute benefit to adjuvant chemotherapy among patients with TNBC compared with those with hormone-positive disease [33].

In an analysis of three randomized trials that involved a total of 6644 women with node-positive breast cancer, compared with those with ER-positive breast cancer, patients with ER-negative breast cancer had the following significant outcomes at five years following adjuvant chemotherapy [33]:

●A larger reduction in the risk of recurrence (55 versus 26 percent). This translated into a higher absolute improvement in DFS (23 versus 7 percent).

●A larger reduction in the risk of death (55 versus 23 percent). This translated into a higher absolute improvement in overall survival (OS; 17 versus 4 percent).

These data emphasize the importance of neo/adjuvant chemotherapy for women with TNBC, who (unlike those with ER-positive or HER2-positive breast cancer) are not eligible for targeted therapies.

Choice of regimen

●Preferred regimen – Anthracycline-, alkylator-, and taxane-based chemotherapy regimens remain the standard regimens for TNBC, for example, dose-dense doxorubicin and cyclophosphamide followed by paclitaxel (AC-T) (table 5). Taxanes have significant activity in the treatment of TNBC, and there are no meaningful data regarding regimens lacking alkylator-based therapy [34-36]. As an example of the benefits of a taxane, in the GEICAM 9906 trial of adjuvant fluorouracil, epirubicin, and cyclophosphamide (FEC) versus FEC followed by paclitaxel, the addition of paclitaxel was associated with an improvement in DFS at seven years (74 versus 56 percent, respectively) [36]. The ABC trials tested anthracycline/taxane-based regimens versus docetaxel and cyclophosphamide (TC) given for the same duration, finding a benefit overall for incorporation of the anthracycline, particularly in TNBC in subset analysis. However, the absolute benefit in node-negative TNBC appears modest [37]. Further discussion of these data is elsewhere. (See "Selection and administration of adjuvant chemotherapy for HER2-negative breast cancer", section on 'Rationale for anthracycline- and taxane-containing regimen'.)

•Non-anthracycline-based regimens are an appropriate alternative for patients with lower-risk TNBC (eg, node-negative, <1 cm, or those with cardiac risk factors) and those who prefer to avoid the risks associated with anthracyclines. TC (table 6) is an alternative in low-risk disease, and is discussed in more detail elsewhere (in patients with HER2-negative disease, irrespective of hormone receptor status). (See "Selection and administration of adjuvant chemotherapy for HER2-negative breast cancer", section on 'Acceptable alternatives to anthracycline-based treatment'.)

For example, in a randomized trial of nearly 650 patients with operable TNBC, those assigned to six cycles of adjuvant paclitaxel and carboplatin (administered on days 1, 8, and 15 every 28 days) had a longer DFS relative to those assigned to an anthracycline and taxane based regimen (five-year DFS 87 versus 80 percent), with similar OS [38].

●Is there a role for an antimetabolite agent? – For patients with stage II or III TNBC, neoadjuvant regimens such as AC-T or TC are standard, followed by capecitabine for those with residual disease, given results of a randomized trial showing an OS benefit with the adjuvant addition of capecitabine when residual disease is present [39]. These results are discussed elsewhere. (See "Selection and administration of adjuvant chemotherapy for HER2-negative breast cancer", section on 'Regimen selection and administration'.)

However, for patients with stage I disease, adjuvant rather than neoadjuvant treatment is appropriate, using standard regimens such as AC-T or TC. In general, for patients who have not received neoadjuvant chemotherapy, adding antimetabolite agents such as capecitabine or gemcitabine to adjuvant chemotherapy has not improved OS outcomes in TNBC [40,41], and it is not our approach. A Chinese trial demonstrated improvement in DFS, but not OS, with capecitabine following standard adjuvant regimens [42]. Among 434 women with early-stage TNBC who received standard adjuvant treatment (94 percent of whom had not received neoadjuvant therapy), low-dose capecitabine maintenance therapy for one year improved five-year DFS compared with observation only (83 versus 73 percent; hazard ratio [HR] 0.64, 95% CI 0.42-0.95). The five-year OS was similar between the groups (86 versus 81 percent, with and without capecitabine, respectively; HR 0.75, 95% CI 0.47-1.19). The trial had important limitations; notably, there was an imbalance in randomization, with a higher proportion of older women assigned to placebo, which could have favored the capecitabine group.

In a separate phase III trial of 876 women with early-stage TNBC who had received standard adjuvant chemotherapy, subsequent treatment with capecitabine versus placebo resulted in numerically, but not statistically, improved five-year DFS and OS (DFS, 80 versus 77 percent, HR 0.79, 95% CI 0.61-1.03; OS, 86.2 versus 85.9 percent, HR 0.92, 95% CI 0.66-1.28) [40]. Similarly, trials looking at adjuvant gemcitabine have proven negative.

Given the sum of data, we opt for standard anthracycline- and/or taxane-based chemotherapy regimens as adjuvant therapy in patients with TNBC who have not received neoadjuvant treatment. As discussed, in practice, only lower-risk patients (ie, stage I TNBC) are treated with adjuvant rather than neoadjuvant chemotherapy, as most patients with higher-risk disease receive neoadjuvant therapy.

●Is there a role for platinums? – There is controversy as to whether adding platinum-based chemotherapy should be "standard" in stage II or III TNBC. Trials have shown that adding platinum-based chemotherapy to neoadjuvant regimens can improve the rate of complete pathologic response [43,44]. However, to date, this has not improved OS in women also receiving anthracycline-, alkylator-, and taxane-based treatment. This is discussed further elsewhere. (See "Choice of neoadjuvant chemotherapy for HER2-negative breast cancer", section on 'Special considerations for triple-negative disease'.)

PARP inhibitors for BRCA carriers — The poly(ADP-ribose) polymerase (PARP) inhibitor olaparib has regulatory approval by the US Food and Drug Administration for the adjuvant treatment of adult patients with deleterious or suspected deleterious germline breast cancer susceptibility gene (BRCA)-mutated, HER2-negative, high-risk early breast cancer who have been treated with neoadjuvant or adjuvant chemotherapy. This is discussed in detail elsewhere. (See "Selection and administration of adjuvant chemotherapy for HER2-negative breast cancer", section on 'BRCA carriers with high-risk disease'.)

Is there a role for immunotherapy? — The incorporation of immunotherapy in neoadjuvant regimens is discussed elsewhere. Pembrolizumab has regulatory approval with chemotherapy for the neoadjuvant treatment of patients with high-risk, early-stage TNBC. (See "Choice of neoadjuvant chemotherapy for HER2-negative breast cancer", section on 'Incorporation of immunotherapy with NACT in TNBC'.)

Treatment of tumors ≤0.5 cm — The prognosis of node-negative, triple-negative tumors ≤0.5 cm is generally favorable, and therefore, the benefits of adjuvant chemotherapy are likely to be very small and must be weighed against the chances of serious side effects of chemotherapy. In general, patients with microinvasive or very small (1 to 5 mm) tumors do not need chemotherapy, although we discuss the issue carefully with such patients, given that a small benefit cannot be ruled out, and, some patients, particularly those with 4 or 5 mm tumors, may reasonably elect to proceed with treatment. (See "Selection and administration of adjuvant chemotherapy for HER2-negative breast cancer", section on 'Special populations'.)

In a retrospective review of almost 4400 patients with small, node-negative TNBCs (6.5 percent with pT1a, 21 percent with pT1b, and 72 percent with pT1c tumors), adjuvant chemotherapy was administered in 53 percent of cases [45]. Patients receiving chemotherapy had more unfavorable baseline characteristics including younger age, larger tumors, and higher tumor grade. In multivariate analysis, adjuvant chemotherapy improved breast cancer-specific survival in the overall group (adjusted HR 0.65, 95% CI 0.48-0.89), but not for the subset of patients with pT1a tumors (adjusted HR 4.28, 95% CI 1.12-16.44). Although limitations of this study include its retrospective nature and that the number of patients with pT1a tumors was small (n = 18), the results suggest that the risks of chemotherapy may outweigh benefits in patients with these small tumors.

The natural history of small triple-negative tumors was demonstrated in a study of 143 patients with triple-negative tumors up to 1 cm in size and not treated with adjuvant chemotherapy [46]. Patients with triple-negative tumors had a 75 to 89 percent relapse-free survival and over 95 percent distant relapse-free survival at five years. Another study including 363 T1a-bN0 triple-negative tumors from the National Comprehensive Cancer Network (NCCN) database suggested a 90 to 93 percent distant relapse-free survival without chemotherapy [47]. Given the lack of prospective data on women who present with small tumors, the decision to administer adjuvant chemotherapy must be individualized based on patient and provider preferences.

Prognosis — The risk of distant recurrence and death peaks approximately three years after diagnosis and declines rapidly thereafter [31]. TNBC is characterized by higher relapse rates during this period of time compared with ER-positive breast cancers, although the latter tend to continue to recur for decades later while TNBCs tend not to do so. Therefore, overall in the long run the absolute risk of recurrence for the two subtypes approach one another. Furthermore, however, TNBC may be more likely to recur in locoregional areas as well as in visceral organs, such as liver, lung, and brain involvement at first recurrence [48-51]. By contrast, TNBC is less likely than ER-positive breast cancer to recur initially in bone [51]. In one study involving 116 patients with triple-negative metastatic breast cancer, brain metastases were the initial site of metastatic disease or occurred during their metastatic course in 14 and 46 percent, respectively [49]. The median survival following a diagnosis of central nervous system metastases is less than six months [52,53].

Patients with TNBC have a poorer short-term (first five to seven years) prognosis compared with patients with other breast cancer subtypes [14,26,51,54]. In a 2012 study of 12,902 women who presented to NCCN centers, compared with women with hormone receptor-positive, HER2-negative breast cancer, women with TNBC experienced, at a median follow-up of three years [51]:

●Worse breast cancer-specific survival (HR 2.99, 95% CI 2.59-3.45).

●Worse OS (HR 2.72, 95% CI 2.39-3.10).

●A dramatic increase in death within two years of diagnosis (HR 6.10, 95% CI 4.81-7.74). However, the magnitude of this risk declined substantially over time (HR of death two to six years from diagnosis 2.30, 95% CI 1.39-3.82; HR of death >6 years from diagnosis 0.86, 95% CI 0.30-2.46). Thus, the risk of recurrence and breast cancer mortality for hormone receptor-positive, HER2-negative disease becomes approximately equal to that of triple-negative cancers within the second decade.

The risk of late recurrence is low for women with TNBC. In a single-center retrospective series of 783 women with stage I, II, or III TNBC who were alive and without recurrence at five years after treatment for the original diagnosis, the yearly recurrence-free interval at 10 and 15 years was 97 and 95 percent, respectively, and the relapse-free survival rates were 91 and 83 percent, respectively [55]. In a prospective cohort study in which patients with stage I to III breast cancer diagnosed between 1986 and 1992 were matched with patients diagnosed between 2004 and 2008, the hazard rate of relapse for those with triple-negative disease had dropped to essentially zero after year 6 among patients treated in the later cohort [56].

Post-treatment surveillance — There are no specific post-treatment surveillance guidelines for patients with TNBC. Patients with breast cancer should undergo a similar surveillance routine according to American Society of Clinical Oncology guidelines following breast cancer treatment, regardless of breast cancer subtype. This should include history and complete physical exam every three months for the first three years, then every 6 to 12 months for surveillance. A further discussion on post-treatment surveillance is covered separately. (See "Approach to the patient following treatment for breast cancer", section on 'Guidelines for post-treatment follow-up'.)

METASTATIC DISEASE — Many of the general principles applicable to advanced breast cancer of other phenotypes apply to that of TNBC. Chemotherapy has been the mainstay of systemic treatment for TNBC, as endocrine therapy and HER2-directed therapies are ineffective. However, several trials have suggested a role for targeted therapies in TNBC including inhibitors of poly(ADP-ribose) polymerase (PARP) and immune checkpoints (algorithm 1). (See "Overview of the approach to metastatic breast cancer" and "Endocrine therapy resistant, hormone receptor-positive, HER2-negative advanced breast cancer".)

Repeat biopsy — In patients with metastatic breast cancer, a confirmatory biopsy of a suspected lesion should be obtained when possible, with the following assessments:

●Reassessment of ER, PR, and HER2 – This is because there is a possible discordance of these markers between primary and metastatic disease [57-61]. As an example of discordance between primary and metastatic lesions, in a pooled analysis of two prospective studies, the rates of discordance in ER, PR, and HER2 between the primary and recurrent disease were 13, 28, and 5 percent, respectively [58].

●PD-L1 expression – The companion diagnostic immunohistochemical assay for programmed cell death ligand 1 (PD-L1)-positive immune cells, the 22C3 pharmDX assay, is used to identify patients for pembrolizumab. (See 'PD-L1 combined positive score of at least 10' below.)

Because the US Food and Drug Administration (FDA) has approved each test as a "companion diagnostic" with a specific immune checkpoint inhibitor rather than approval as a class, either of the companion diagnostics is acceptable.

●TMB, MSI, and dMMR – Additionally, tumor mutational burden (TMB), microsatellite instability (MSI), and mismatch repair deficiency (dMMR) should be performed if there is sufficient tissue. Further details of testing are found elsewhere. (See "Tissue-agnostic cancer therapy: DNA mismatch repair deficiency, tumor mutational burden, and response to immune checkpoint blockade in solid tumors", section on 'Assessing mismatch repair' and "Tissue-agnostic cancer therapy: DNA mismatch repair deficiency, tumor mutational burden, and response to immune checkpoint blockade in solid tumors", section on 'Approach to testing dMMR as a predictive marker'.)

However, if needed, these assessments can instead be performed in a subsequent biopsy after progression, given that they will not dictate choice of initial therapy and that these abnormalities are relatively rare in breast cancer. (See 'Pembrolizumab for tumors with high TMB or MSI-H/dMMR tumors' below.)

In addition to these assays performed on tissue biopsy, all patients with TNBC should undergo genetics evaluation to determine if they are breast cancer susceptibility gene (BRCA) carriers, given the therapeutic implications in advanced disease. (See 'No germline BRCA mutation' below and 'Germline BRCA mutation' below.)

Initial treatment for rapidly progressive visceral disease — Combination chemotherapy may be appropriate for those with extensive or rapidly progressive visceral disease, in whom the higher chance of response is thought to outweigh the higher risks of toxicity, due to concerns about impending organ dysfunction. However, both clinicians and patients should know there are no prospective data that show combination chemotherapy improves overall survival (OS) compared with single-agent sequential cytotoxic chemotherapy. Further details are discussed elsewhere. (See "Endocrine therapy resistant, hormone receptor-positive, HER2-negative advanced breast cancer", section on 'Combination versus single agent chemotherapy'.)

Initial treatment in the absence of rapidly progressive visceral disease — As discussed above, patients with metastatic TNBC should have germline testing for BRCA, as well as tumor assessment for PD-L1. (See 'Genetics evaluation' above and 'Repeat biopsy' above.)

The initial treatment approach depends on the outcomes of these assessments.

No germline BRCA mutation

PD-L1 combined positive score <10 — Our approach to most patients with advanced, sporadic, triple-negative metastatic breast cancer with programmed cell death ligand 1 (PD-L1) combined positive score (CPS) <10 is to use single-agent chemotherapy. However, combination chemotherapy strategies may be appropriate in some such patients with rapidly progressive visceral disease.

Either platinum- or non-platinum-based regimens are appropriate, with a choice driven by toxicity profiles. In a meta-analysis of 10 randomized trials comparing platinum-containing chemotherapy with regimens not containing platinum in 958 women with metastatic TNBC, the death rate at one year in the platinum group was 46 versus 51 percent in the non-platinum group (hazard ratio [HR] 0.85, 95% CI 0.73-1.00) [62]. However, grade 3 and 4 toxicities were higher among platinum recipients, including nausea/vomiting (relative risk [RR] 4.8) and anemia (RR 3.8).

Outcomes of platinum and non-platinum regimens in breast cancer susceptibility gene (BRCA)-associated TNBCs are discussed below. (See 'Chemotherapy-naϊve patients, or those with progression on PARP inhibitors' below.)

Further lines of chemotherapy are similar to patients with hormone receptor-positive, HER2-negative disease and are discussed elsewhere. (See "Endocrine therapy resistant, hormone receptor-positive, HER2-negative advanced breast cancer".)

PD-L1 combined positive score of at least 10 — Pembrolizumab is approved by the FDA in combination with chemotherapy for patients with metastatic TNBC whose tumors express PD-L1 with a CPS ≥10 (the percentage of total cells [tumor cells, lymphocytes, macrophages] that stain for PD-L1) [63].

Although pembrolizumab is used irrespective of treatment line, the supporting data were based on patient experiences receiving first-line treatment for metastatic disease.

In KEYNOTE 355, 847 patients with locally recurrent, inoperable, or metastatic TNBC, all of whom had a disease-free interval of ≥6 months, were randomly assigned to chemotherapy (nabpaclitaxel, paclitaxel, or gemcitabine/carboplatin), with or without pembrolizumab [64]. Overall, there was a modest improvement in median progression-free survival (PFS) with the addition of pembrolizumab (7.5 versus 5.6 months; HR 0.82, 95% CI 0.69-0.97). Results were also stratified according to CPS. In patients with CPS ≥10, the addition of pembrolizumab to chemotherapy improved median PFS by approximately four months (9.7 versus 5.6 months; HR 0.65, 95% CI 0.49-0.86). Among patients with CPS ≥1, median PFS was 7.6 versus 5.6 months with and without pembrolizumab, a difference that was not statistically significant (HR 0·74, 95% CI 0.61-0.90). In subsequent reporting, addition of pembrolizumab improved OS among patients with a CPS ≥10 (23.0 versus 16.1 months; HR 0.73, 95% CI 0.55-0.95) [65]. Although there were also improvements in PFS among those with CPS ≥1, there was no statistically significant OS improvement in this subgroup (17.6 versus 16 months).

Grade 3 to 4 adverse events were comparable between the two groups (approximately 70 percent), although one patient in the pembrolizumab arm died from treatment-related toxicity.

Atezolizumab was previously granted accelerated approval by the FDA in combination with nabpaclitaxel for those with advanced TNBC with PD-L1-stained, tumor-infiltrating immune cells of any intensity covering ≥1 percent of the tumor area, but this approval was withdrawn due to lack of improvement in PFS in IMpassion 131 [66], despite an OS and PFS benefit in IMpassion 130 [67,68].

In addition to the chemotherapy combination trials noted above, early clinical experience with immunotherapy in the setting of TNBC also includes small studies of the single-agent anti-programmed cell death protein-1 (PD-1) antibody pembrolizumab as well as anti-PD-L1 antibodies avelumab and atezolizumab [69-71], with response rates generally <20 percent even in PD-L1-selected tumors. Additional strategies, including combination immunotherapy with other systemic therapy or with radiation, as well as other approaches, are in development. Furthermore, optimization of biomarkers predictive of response to immunotherapy is actively under investigation.

Germline BRCA mutation

Patients with previous exposure to chemotherapy — Inhibitors of PARP may be particularly useful in breast cancer susceptibility gene (BRCA)-mutated breast cancers, of which the majority are triple negative. For most patients with TNBC with germline BRCA mutations who have previously been treated with chemotherapy in the neoadjuvant, adjuvant, or metastatic disease setting, we suggest an oral inhibitor of PARP rather than chemotherapy, since the data suggest improved efficacy and fewer side effects. However, chemotherapy is appropriate if and when a patient suffers progressive disease on a PARP inhibitor; or for those who are chemotherapy naive, having never received chemotherapy either in the early-stage or metastatic setting; or, as discussed above, for those with rapidly progressive visceral disease. (See 'Initial treatment for rapidly progressive visceral disease' above.)

Additionally, the combination of immunotherapy and chemotherapy is an acceptable alternative to a PARP inhibitor for those with PD-L1-positive disease. (See 'Chemotherapy-naϊve patients, or those with progression on PARP inhibitors' below and 'PD-L1 combined positive score of at least 10' above.)

In the OlympiAD trial, among the subset of 121 BRCA mutation carriers with metastatic triple-negative disease, all of whom had received an anthracycline and a taxane in either the adjuvant or metastatic setting, those randomly assigned to olaparib experienced an improved PFS relative to those receiving chemotherapy (HR for progression or death 0.43, 95% CI 0.29-0.63) [72]. The overall study, which also included those with hormone receptor-positive, HER2-negative disease, was also positive, but the improvements noted with olaparib were stronger in the triple-negative population. Similarly, in the TNBC subgroup of the EMBRACA trial, which also enrolled patients with advanced breast cancer and a germline BRCA mutation, talazoparib improved PFS relative to single-agent chemotherapy (HR 0.60, 95% CI 0.41-0.87). Further details of these studies are discussed elsewhere. It should be noted that the comparator single-agent chemotherapy options did not include either taxanes or platinums in these studies, so the trial realistically only compared PARP inhibitors against second-line therapies. It is unknown how PARP inhibitors would compare with first-line drugs. (See "Overview of the approach to metastatic breast cancer", section on 'Special considerations'.)

There are several other PARP inhibitors in clinical development [73-79]. For example, veliparib (ABT-888) was tested in combination with temozolomide, an alkylating agent, among 41 women with advanced TNBC (of whom 8 had a BRCA germline mutation) in a single-arm phase II study [79]. While the overall response and clinical benefit rates were 7 and 17 percent across the entire study population, any activity appeared to be concentrated among the patients with BRCA mutations, in whom the overall response and clinical benefit rates were 37.5 and 62.5 percent, respectively. The results of the ISPY trial that evaluated the combination of veliparib plus carboplatin when combined with standard chemotherapy as part of a neoadjuvant treatment program in women with TNBC are discussed elsewhere. (See "Choice of neoadjuvant chemotherapy for HER2-negative breast cancer", section on 'Special considerations for triple-negative disease'.)

There is mechanistic rationale for use of PARP inhibition as anticancer therapy. PARP is involved in the molecular events leading to cell recovery from DNA damage. When PARP1, the most abundant member of the PARP family, is inhibited, double-strand DNA breaks accumulate and under normal conditions are repaired via the BRCA pathway-dependent homologous recombination mechanism [80]. Investigators hypothesized that inhibition of PARP, in combination with DNA-damaging chemotherapeutics, would render tumors lacking BRCA function exquisitely sensitive, a hypothesis that has borne out in both the preclinical and clinical arenas [73,81-83]. Given the shared clinicopathologic characteristics between BRCA-mutated breast cancer and TNBCs, the efficacy and safety of PARP inhibition is being tested in both settings. However, PARP inhibitors remain investigational for sporadic TNBC.

Chemotherapy-naϊve patients, or those with progression on PARP inhibitors — Although we typically start with a poly(ADP-ribose) polymerase (PARP) inhibitor for metastatic disease in those with germline BRCA mutations who have had chemotherapy in the (neo)adjuvant setting, chemotherapy is the preferred option for those who have never been exposed to chemotherapy (in the early or metastatic settings); or for those who have experienced progression on a PARP inhibitor; or for those with rapidly progressive visceral disease, as discussed above. (See 'Initial treatment for rapidly progressive visceral disease' above.)

When administering chemotherapy, our approach is as follows:

●For the subset of patients with BRCA-associated breast cancers that also express PD-L1 with CPS ≥10, we recommend immunotherapy plus chemotherapy as the initial chemotherapy regimen, over other chemotherapy options. (See 'PD-L1 combined positive score of at least 10' above.)

●However, for those with BRCA-associated cancers with PD-L1 CPS<10, chemotherapy rather than chemoimmunotherapy is appropriate. Both platinums and taxanes are considered appropriate options for chemotherapy, with a choice driven by scheduling and toxicity considerations. Guidelines from the American Society of Clinical Oncology have, however, suggested platinum agents over taxanes for BRCA1/2 carriers with advanced breast cancers [84], based on a randomized trial of carboplatin versus docetaxel in first-line therapy of TNBC described below.

The TNT randomized trial directly compared carboplatin and docetaxel in the first-line treatment setting for women with metastatic TNBC. Overall response rates were similar in the overall group, but among the 43 women with a known BRCA1/2 mutation, carboplatin resulted in a higher response rate (68 versus 33 percent; absolute difference 35 percent, 95% CI 6.3-63.1 percent) and PFS (6.8 versus 4.4 months; absolute difference 2.6 months, 95% CI 0.11-5.12 months) [85]. However, the trial had a crossover design, and no statistically significant OS difference was seen (12.8 months, 95% CI 10.6-15.3; and 12 months, 95% CI 10.2-13) for those allocated carboplatin or docetaxel, respectively, suggesting that either agent may be administered first, without compromising outcomes.

Grade ≥3 toxicities among those receiving carboplatin versus docetaxel included febrile neutropenia in 2 and 20 percent, diarrhea in 3 and 7 percent, and thrombocytopenia in 7 and 0 percent, respectively. Any-grade toxicities for carboplatin versus docetaxel included alopecia in 35 and 89 percent, arthralgias in 4 and 21 percent, diarrhea in 34 and 64 percent, and peripheral neuropathy in 33 and 71 percent, respectively. Fatigue occurred in 95 percent in both arms.

Later-line options

Fam-trastuzumab deruxtecan in HER2-"low" cancers — Fam-trastuzumab deruxtecan has regulatory approval in the United States for patients with advanced HER2-low (immunohistochemistry [IHC] 1+ or IHC 2+/in situ hybridization-negative) breast cancer who have received a prior chemotherapy in the metastatic setting or developed disease recurrence during or within six months of completing adjuvant chemotherapy. This is discussed in detail elsewhere. (See "Overview of the approach to metastatic breast cancer", section on 'HER2-low tumors'.)

Sacituzumab govitecan — Trop-2 is expressed in the majority of TNBCs. Sacituzumab govitecan is an antibody-drug conjugate that targets Trop-2 for the selective delivery of SN-38, the active metabolite of irinotecan. It is approved by the FDA for the treatment of adult patients with unresectable locally advanced or metastatic TNBC who have received at least two prior therapies, at least one of them for metastatic disease [86]. Severe neutropenia and diarrhea may occur with this agent, including cases of neutropenic colitis. Management of enterotoxicity of this agent is discussed elsewhere. (See "Clinical presentation and risk factors for chemotherapy-associated diarrhea, constipation, and intestinal perforation", section on 'Sacituzumab govitecan'.)

A randomized trial enrolled patients with metastatic TNBC that was relapsed or refractory to two or more previous standard chemotherapy regimens; prior therapy had to include a taxane (for any indication) [87]. Among 468 patients, those assigned to sacituzumab govitecan had improved OS compared with those assigned to clinician's choice of chemotherapy (12.1 versus 6.7 months; HR 0.48, 95% CI 0.38-0.59). They also experienced improvements in PFS (5.6 versus 1.7 months; HR 0.41, 95% CI 0.32-0.52) and objective response rate (35 versus 5 percent). The rates of key grade ≥3 treatment-related adverse events were as follows: neutropenia (51 percent with sacituzumab govitecan and 33 percent with chemotherapy), leukopenia (10 and 5 percent), diarrhea (10 and <1 percent), anemia (8 and 5 percent), and febrile neutropenia (6 and 2 percent).

Results were consistent with a previous single-arm trial [88].

Pembrolizumab for tumors with high TMB or MSI-H/dMMR tumors — The immune checkpoint inhibitor pembrolizumab is approved by the FDA for the treatment of unresectable or metastatic, microsatellite instability-high (MSI-H) or mismatch repair-deficient (dMMR) solid tumors, as well as tumors with high tumor mutational burden (TMB), that have progressed following prior treatment and that have no satisfactory alternative treatment options. We offer pembrolizumab for immunotherapy-naïve patients with these molecular markers, but only when chemotherapy (and PARP inhibitors, for BRCA carriers) is no longer effective or tolerated. Testing for TMB and dMMR is discussed elsewhere. (See "Tissue-agnostic cancer therapy: DNA mismatch repair deficiency, tumor mutational burden, and response to immune checkpoint blockade in solid tumors", section on 'Assessing mismatch repair' and "Tissue-agnostic cancer therapy: DNA mismatch repair deficiency, tumor mutational burden, and response to immune checkpoint blockade in solid tumors", section on 'Approach to testing for high levels of TMB'.)

We acknowledge, in discussion with patients, that the trials supporting the approval of pembrolizumab for these indications did not include breast cancer patients, but efficacy was demonstrated in other cancer types, including cervical, endometrial, and ovarian cancer. (See "Tissue-agnostic cancer therapy: DNA mismatch repair deficiency, tumor mutational burden, and response to immune checkpoint blockade in solid tumors", section on 'Other tumors with MSI-H/dMMR' and "Tissue-agnostic cancer therapy: DNA mismatch repair deficiency, tumor mutational burden, and response to immune checkpoint blockade in solid tumors", section on 'Tumors with high mutational burden'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Hereditary breast and ovarian cancer" and "Society guideline links: Breast cancer".)

SUMMARY AND RECOMMENDATIONS

●Introduction

•Triple-negative breast cancer (TNBC) lacks expression of the three most commonly evaluated biomarkers (the estrogen receptor [ER], progesterone receptor [PR], and the human epidermal growth factor receptor 2 [HER2] protein). (See 'Introduction' above.)

•TNBCs are typically higher grade, and are more likely to be diagnosed clinically rather than mammographically than ER-positive cancers. (See 'Clinical presentation' above.)

•While the triple-negative clinical phenotype is heterogeneous, the basal-like molecular subtype comprises a large proportion, particularly for breast cancer susceptibility gene 1 (BRCA1)-associated breast cancer. (See 'Pathologic characteristics' above.)

●Non-metastatic disease

•The principles that apply to the surgical treatment and use of radiation therapy in breast cancer, and the systemic treatment approach in both the neoadjuvant and adjuvant settings, are similar in TNBC and other HER2-negative subtypes. (See 'Non-metastatic disease' above.)

•For patients with TNBC and either a tumor size >0.5 cm or pathologically involved lymph nodes (regardless of tumor size), we recommend chemotherapy (Grade 1B), to be administered in either the adjuvant or neoadjuvant setting. Risk of recurrence increases on a continuum, such that larger tumors are more likely to derive benefit from chemotherapy than smaller ones. In general, patients with tumors 1 to 5 mm do not need chemotherapy, although we discuss the issue carefully with such patients, given that a small benefit cannot be ruled out. (See 'Treatment of tumors ≤0.5 cm' above.)

-For most patients receiving chemotherapy for non-metastatic TNBC, we suggest an anthracycline- and taxane-based combination, such as dose-dense doxorubicin and cyclophosphamide followed by paclitaxel (AC-T (table 5)) rather than a non-anthracycline-based treatment (Grade 2B). Although no regimen has proved to be superior to AC-T, the non-anthracycline-based regimen docetaxel and cyclophosphamide (TC (table 6)) is an appropriate alternative for patients who have indications for chemotherapy but have lower-risk disease.

-Decisions regarding administration in the neoadjuvant versus adjuvant setting are found elsewhere. (See "General principles of neoadjuvant management of breast cancer", section on 'Patient selection'.)

-For patients who have completed a full course of neoadjuvant treatment, additional chemotherapy in the adjuvant setting for those with residual disease is discussed elsewhere. (See "Selection and administration of adjuvant chemotherapy for HER2-negative breast cancer", section on 'Patients who received neoadjuvant treatment'.)

•Despite a higher risk of relapse compared with other breast cancer subtypes, there are no specific post-treatment surveillance guidelines for patients with TNBC; American Society of Clinical Oncology surveillance guidelines apply similarly across subtypes. (See 'Post-treatment surveillance' above.)

●Metastatic disease

•Combination chemotherapy for those with rapidly progressive visceral disease – In the metastatic setting, combination chemotherapy may be appropriate for those with extensive or rapidly progressive visceral disease, in whom the higher chance of response is thought to outweigh the higher risks of toxicity. However, there are no prospective data that show combination chemotherapy improves overall survival (OS) compared with single-agent sequential cytotoxic chemotherapy. (See "Endocrine therapy resistant, hormone receptor-positive, HER2-negative advanced breast cancer", section on 'Combination versus single agent chemotherapy'.)

•Single agent chemotherapy for those who are not in visceral crisis – In the metastatic TNBC setting, for those who are not in visceral crisis, therapy depends on prior treatment history, programmed cell death ligand 1 (PD-L1) expression, and germline BRCA mutation status (algorithm 1).

-PD-L1 CPS ≥10 – For TNBC with PD-L1 combined positive score (CPS) ≥10 (in BRCA-wildtype patients, as well as in chemotherapy-naïve germline BRCA carriers), we suggest the combination of pembrolizumab and chemotherapy as initial treatment for metastatic disease, rather than single-agent chemotherapy (Grade 2B). (See 'PD-L1 combined positive score of at least 10' above and 'Chemotherapy-naϊve patients, or those with progression on PARP inhibitors' above.)

-PD-L1 CPS <10 – For TNBC with PD-L1 CPS <10 (in BRCA-wildtype patients, as well in chemotherapy-naïve BRCA carriers), single-agent chemotherapy remains the preferred initial treatment option and is discussed elsewhere. Pembrolizumab is an appropriate later-line option for those whose tumors have either high tumor mutational burden (TMB) or are microsatellite instability high or mismatch repair deficient (dMMR). (See 'PD-L1 combined positive score <10' above.)

•BRCA carriers with previous exposure to chemotherapy – For BRCA carriers with previous exposure to chemotherapy in the neoadjuvant/adjuvant setting, we suggest an inhibitor of poly(ADP-ribose) polymerase (PARP) as initial treatment for metastatic disease (Grade 2B), although chemotherapy is also acceptable, particularly in those with PD-L1-positive disease, in whom chemotherapy plus an immune checkpoint inhibitor is an appropriate alternative. (See 'Germline BRCA mutation' above.)

•Later line option – Sacituzumab govitecan is an antibody-drug conjugate that targets Trop-2 for the selective delivery of SN-38, the active metabolite of irinotecan, and is an option for patients with metastatic TNBC who have received at least two prior therapies, at least one of which was for metastatic disease. (See 'Sacituzumab govitecan' above and 'Pembrolizumab for tumors with high TMB or MSI-H/dMMR tumors' above.)