Relatively few clinically important therapeutic advances have occurred in the treatment of triple-negative breast cancer (TNBC) since the introduction of taxanes as adjuvant therapy over 20 years ago. However, this is rapidly changing due to a variety of conceptually important clinical trials and emerging new options such as immune checkpoint inhibitors and antibody-drug conjugates. Evidence also increasingly supports that platinum drugs and inhibitors of poly (ADP-ribose) polymerase, or PARP, are particularly effective in the treatment of germline BRCA-mutant cancers, including TNBC. An important development in early-stage TNBC was the recognition that extensive residual cancer after neoadjuvant chemotherapy identifies patients who remain at high risk for recurrence. This has led to the design of two ongoing adjuvant trials (one testing pembrolizumab, the other investigating platinum drugs and capecitabine) that offer a “second chance” to improve the survival of patients with residual cancer after neoadjuvant chemotherapy. Genomic analysis of TNBC has revealed large-scale transcriptional, mutational, and copy number heterogeneity, without any frequently recurrent mutations, other than TP53. Consistent with this molecular heterogeneity, most targeted agents, so far, have demonstrated low overall activity in unselected TNBC, but important “basket” trials are ongoing.
Introduction
Triple-negative breast cancer (TNBC) accounts for 15% to 20% of all breast cancers. It is defined by the lack of estrogen receptor (ER) and progesterone receptor (PR) expression, and normal human epidermal growth factor receptor 2 (HER2) receptor gene copy number and expression.[1] The clinical course of TNBC and the risk factors that predispose to development of this disease differ from ER-positive cancers. Multiple and early pregnancies, as well as lack of breastfeeding, have been suggested as reproductive risk factors for TNBC.[2,3] Interestingly, some of these same parameters are protective against ER-positive cancers. Distant metastatic recurrences tend to occur within the first 3 to 5 years after the diagnosis of TNBC. Late recurrences are relatively rare, unlike in ER-positive cancers, in which up to 50% of distant recurrences develop after 5 years. The prevalence of TNBC is higher among younger women and African-American women.[4,5] The cause of this higher prevalence among African Americans is unknown; reproductive and breastfeeding practices may contribute, as well as other yet-to-be identified lifestyle and genomic factors.[3,4] A subset of TNBCs are highly sensitive to chemotherapy, which is indicated by the 30% to 35% rates of pathologic complete response (pCR, defined as no residual invasive cancer in the breast and lymph nodes [ypT0/ypN0]) after neoadjuvant chemotherapy. The corresponding rates of pCR in ER-positive cancers range from 10% to 25% depending on the proliferation rate of the cancer.[6] While TNBC is widely held to be particularly aggressive and lethal, in fact, the majority of patients with early-stage TNBC will never experience a distant metastatic recurrence or die from their disease.[7] However, the survival duration of patients with metastatic TNBC is notably shorter (median, 12 to 18 months) than that of patients with metastatic ER-positive cancers (median, 50 to 60 months).[8]
Heterogeneity in TNBC
Most TNBCs are invasive ductal carcinomas, although a minority represent rare histologic subtypes such as medullary carcinoma, metaplastic carcinoma, and adenoid cystic carcinoma.[9] Most TNBC tissue samples evaluated by gene expression profiling are classified as the basal-like molecular subtype. However, genomic analysis reveals substantial transcriptional, mutational, and copy number heterogeneity within TNBC tumors.[10] Several molecular subclassifications of TNBC have been proposed based on gene expression profiling; not surprisingly, however, the greater molecular heterogeneity of this cancer type limits the reproducibility and concordance between different classification methods.[11] One of the most frequently used subclassifications was proposed by Lehmann et al and included six subtypes: two basal-like (BL1 and BL2), immunomodulatory (IM), mesenchymal (M), mesenchymal stem–like (MSL), and a luminal androgen receptor (LAR) subtype. More recently, the same investigators revised the classification system into four subtypes only, including BL1, BL2, M, and LAR.[12] The clinical relevance of these subtypes is yet to be defined in prospective studies. Nevertheless, several potentially therapeutically important TNBC subgroups are emerging, and these can often be defined by simple methods.
The Currently Most Therapeutically Relevant Subtypes of TNBC
Approximately 70% of TNBCs contain 20% or more tumor infiltrating lymphocytes (TILs) in the tumor stroma. The more TILs present in the stroma, the better the prognosis.[13,14] However, while immune-rich TNBC has a more favorable prognosis, it is still not good enough to warrant withholding adjuvant chemotherapy, particularly since these cancers also have higher chemotherapy sensitivity and higher rates of pCR after preoperative chemotherapy. In the future, combined multivariate prognostic scores might be developed-based on TIL count, tumor size, nodal status, age, and adjuvant therapy regimen used-that could predict which TNBC patients will be cured and which remain at risk for recurrence despite receiving the best current standard of care. The generally higher level of TILs and higher expression of immune checkpoint molecules in TNBC compared with ER-positive cancers also makes TNBC an attractive target for immunotherapy.[15-17]
Androgen receptor (AR)-positive TNBC accounts for approximately 10% of all TNBCs and tends to have a more indolent course.[12] These cancers are defined by AR expression that can be detected either by immunohistochemistry or by gene expression analysis. AR-positive TNBCs share some features of ER-positive breast cancers, including expression of several estrogen-regulated genes and frequent PIK3CA mutations. Antiandrogens are being investigated as potential treatment in this subset.
Germline BRCA-mutant TNBCs represent another potentially therapeutically relevant subtype. Germline BRCA1 and BRCA2 mutations are more frequent in TNBC (affecting up to 30% of TNBCs) than in other breast cancer subtypes. Because of the relatively high prevalence of BRCA mutations in TNBC, even in the absence of a strong family history, germline BRCA mutation screening is recommended for patients who develop TNBC before or at 60 years of age.[18] Approximately 80% of breast cancers that develop in germline BRCA1-mutation carriers are triple-negative cancers, and about 50% of breast cancers in BRCA2-mutation carriers are TNBCs.[19] The BRCA mutation status is increasingly therapeutically relevant beyond consideration of prophylactic mastectomy/oophorectomy and surveillance.[20] There is mounting evidence that germline BRCA-mutant breast cancers have above-average platinum sensitivity and increased sensitivity to poly (ADP-ribose) polymerase (PARP) inhibitors.[21-23]
We will highlight some current clinical trials (see Table) and examine the data in more detail, placing selected results into the context of treatment decisions, as space limitations permit. For additional information about newer agents under investigation as treatment for TNBC, we recommend two recent comprehensive reviews in this field by Bianchini et al[24] and Sharma.[25]
Therapies for Early-Stage TNBC
Adjuvant vs neoadjuvant therapy
A series of large randomized clinical trials in the 1990s established that adjuvant and neoadjuvant administration of the same chemotherapy regimen yields similar results in disease-free and overall survival.[26] Due to logistical reasons, referral patterns, and patient preferences, the adjuvant use of chemotherapy remained predominant in routine practice.[27] However, we also learned that patients with TNBC who achieve pCR after neoadjuvant chemotherapy have excellent survival, and those who have residual disease are at high risk for recurrence.[28] Therefore, by simply altering the sequence of therapy, one can uncover important prognostic information about the efficacy of a particular chemotherapy regimen in an individual patient treated with curative intent for early-stage disease.
Every clinical trial examining distant recurrence–free survival as a function of pathologic response to neoadjuvant chemotherapy has observed that individuals who achieve pCR have a greater than 90% rate of distant recurrence–free survival.[29] There used to be controversy about how to translate improvements in pCR rate to expected improvement in trial arm–level survival; however, many of the observed results are explained by simple mathematics of proportions of patients in response groups, baseline prognostic risk, and effects of competing therapies on survival.[30] At the individual patient level, it is clear that it is better to be in the pCR group than in the residual disease group, which motivates clinical trials to improve pCR rates. The current highest pCR rates, about 40% to 45%, are achieved by taxane/anthracycline sequential chemotherapy regimens and inclusion of platinum drugs with the taxane component. Inclusion or substitution of other chemotherapy drugs (capecitabine, gemcitabine, vinorelbine, or ixabepilone) resulted in little or no improvement in pCR rates.[31] This is in stark contrast to the doubling of pCR rates in HER2-positive cancers achieved by including trastuzumab and pertuzumab with sequential taxane/anthracycline chemotherapy, which has produced pCR rates above 70%.[32]
Since the presence of residual disease after completion of neoadjuvant therapy predicts poor prognosis, numerous clinical trials are designed to test the value of further adjuvant therapy in TNBC patients with residual disease. Preliminary results of the CREATE-X (JBCRG-04) trial by the Japan Breast Cancer Research Group were presented at the 2015 San Antonio Breast Cancer Symposium.[33] Investigators randomized 910 patients to observation vs 8 cycles of capecitabine therapy, and reported improved rates of 2-year disease-free (87.3% vs 80.5%; P = .001) and overall survival (96.2% vs 93.9%; P = .086) with capecitabine. All of the observed benefit was driven by the improved outcome in the ER-negative subpopulation (n = 296) of the study. Two ongoing US studies examine the value of more chemotherapy or immunotherapy as adjuvant treatment for patients with residual TNBC after neoadjuvant chemotherapy. The EA1131 trial (ClinicalTrials.gov identifier: NCT02445391) by the ECOG-ACRIN Cancer Research Group randomizes patients to either capecitabine or carboplatin for 6 cycles. The S1418/BR006 trial (ClinicalTrials.gov identifier: NCT02954874) conducted jointly by the Southwest Oncology Group (SWOG) and the National Surgical Adjuvant Breast and Bowel Project/Radiation Therapy Oncology Group/Gynecologic Oncology Group (NRG) randomizes patients to observation or 1 year of pembrolizumab adjuvant therapy. The availability of capecitabine as adjuvant chemotherapy based on the CREATE-X trial results and the opportunity to participate in the aforementioned two clinical trials make neoadjuvant chemotherapy the preferred option for TNBCs that require systemic therapy.
Emerging Therapies in Early-Stage TNBC
Platinum-based therapy
At least three randomized studies have examined the addition of platinum agents, under various schedules, to anthracycline/taxane neoadjuvant chemotherapy. Each of the platinum-based regimens demonstrated statistically significantly higher pCR rates (41% vs 54%; 37% vs 53%; 26% vs 51%), albeit with greater hematologic and neurologic toxicity.[34-36] The evidence consistently shows that 10% to 20% of patients with TNBC who would not experience pCR following treatment with a current third-generation taxane and anthracycline will achieve pCR when a platinum drug is added to the regimen. However, because of the substantial added toxicity and predicted modest overall survival benefit across patient subgroups, carboplatin and cisplatin have not been routinely incorporated into neoadjuvant treatment in this disease setting. Several large, ongoing randomized trials are testing the value of adding a platinum drug to current standard-of-care adjuvant chemotherapy, including the NRG-BR003 trial (ClinicalTrials.gov identifier: NCT02488967) and similar studies in China and Korea.
Several lines of evidence from preclinical studies and clinical trials indicate that patients with germline BRCA mutations have above-average sensitivity to platinum agents.[22,37] A number of ongoing neoadjuvant trials are trying to define the role of adding carboplatin (ClinicalTrials.gov identifiers: NCT02032277, NCT02125344), or assessing whether substituting it for doxorubicin (ClinicalTrials.gov identifier: NCT02413320) improves outcomes, in patients with germline BRCA wild-type or mutant TNBC. When no clinical trial option exists, we include carboplatin with weekly paclitaxel, followed by dose-dense doxorubicin and cyclophosphamide, in the neoadjuvant chemotherapy regimens for patients with stage II to III TNBC and germline BRCA mutations, but not for all patients with TNBC.
PARP inhibitor therapy
A very important large adjuvant trial is currently open for patients with germline BRCA-mutant TNBC and high-risk ER-positive cancers; after completion of current standard-of-care therapy, patients are randomized to observation vs 1 year of single-agent therapy with the PARP inhibitor olaparib (ClinicalTrials.gov identifier: NCT02032823). The neoadjuvant I-SPY 2 multiarm trial (ClinicalTrials.gov identifier: NCT01042379) evaluates whether adding talazoparib to paclitaxel increases pCR rates. In another neoadjuvant study (ClinicalTrials.gov identifier: NCT02282345), patients receive single-agent talazoparib for 6 cycles prior to administration of physician’s choice standard chemotherapy for germline BRCA-mutant breast cancer. A trial for patients with partial response to neoadjuvant chemotherapy randomizes between placebo or veliparib in conjunction with breast irradiation before surgery (ClinicalTrials.gov identifier: NCT01618357).
Immune checkpoint inhibitor therapy
Immune checkpoint inhibitors entered clinical testing in early-stage TNBC with unprecedented rapidity. The first patient was enrolled in a neoadjuvant phase I/II trial exploring an anti–programmed death ligand 1 antibody added to standard-of-care chemotherapy before the first single-agent, phase I trial results in metastatic TNBC were published.[38] Currently, there are several neoadjuvant immunotherapy trials (ClinicalTrials.gov identifiers: NCT02489448, NCT02620280, NCT02530489) and one large randomized adjuvant trial (SWOG-S1418) open for accrual for patients with TNBC. This rapid development of immunotherapy drugs with curative intent in early-stage breast cancer-before mature phase II and III trial results became available from studies in metastatic disease-was made possible by the substantial safety experience with use of these agents in other diseases.
Therapies for Metastatic TNBC
It has been difficult to detect improvement in survival of patients with metastatic TNBC over the past 20 years. During the same time period, however, survival has steadily improved for patients with ER- and HER2-positive metastatic cancers due to the introduction of novel endocrine therapies and HER2-targeted drugs. Sequential chemotherapies remain the only routine treatment options for TNBC. The microtubule-targeting agent eribulin is one of the few newer chemotherapy drugs that demonstrated improved survival in a randomized trial including patients with TNBC who received at least two prior lines of chemotherapy.[39] In addition, two large phase III studies demonstrated a survival benefit from eribulin in the metastatic setting, compared with physician’s choice chemotherapy.[40,41]
Because many BRCA wild-type TNBCs display molecular features of homologous DNA recombination deficiency and harbor alterations in a diverse set of DNA repair genes (eg, ATM, RAD51), there were high expectations that platinum drugs and PARP inhibitors would have broad activity in TNBC, beyond the germline BRCA-mutant subset.[42-44] However, randomized trial data suggest that while platinum drugs do have single-agent activity in patients with TNBC, they are not more effective than taxanes-except in germline BRCA-mutant cancers. The most convincing evidence for the greater platinum sensitivity of germline BRCA-mutant breast cancer was provided by the randomized multicenter Treating to New Targets (TNT) trial from the United Kingdom, which compared single-agent docetaxel with single-agent carboplatin as first-line therapy for metastatic TNBC. Overall, there was no difference in efficacy, but among patients with germline BRCA-mutant disease, carboplatin produced superior response rates (63% vs 38% with docetaxel; P = .03) and longer progression-free survival (6.8 months; 95% CI, 4.4–8.1 months vs 3.1 months; 95% CI, 2.4–4.2 months).[21]
The diversity and rarity of potentially targetable mutations in TNBC slow the progress of developing biologically targeted therapies for this disease.[45] Alterations in the phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) signaling pathway are relatively frequent in TNBC, although often different members of the signaling pathway are affected in different individuals.[46,47] In ongoing clinical trials, platinum agents (ClinicalTrials.gov identifier: NCT01931163) and PARP inhibitors (ClinicalTrials.gov identifier: NCT01623349) are being tested in combination with the mTOR inhibitor everolimus and a pan-PI3K inhibitor, respectively, since they showed synergistic activity in preclinical testing in cell lines and xenograft models.[48]
PARP inhibitors
Single-agent PARP inhibitors have shown objective tumor response rates between 10% and 30% in metastatic germline BRCA-mutant breast cancers, with less, or no, activity in BRCA wild-type cancers, in phase I/II trials.[42,49] The most extensively studied PARP inhibitor in breast cancer is olaparib; objective response rates with this drug range between 8% and 22% in various small studies.[50] Indirect comparison of tumor responses across different germline BRCA-mutant cancers suggests that not all tumor types may be equally sensitive to these agents; for example, ovarian cancers consistently show the highest rates of response to olaparib.[51] A large randomized trial comparing single-agent olaparib with physician’s choice chemotherapy for germline BRCA-mutant metastatic breast cancers (ClinicalTrials.gov identifier: NCT02000622) has completed accrual. The results are expected to be available soon and will have a major impact on this field. A number of trials are also exploring PARP inhibitors administered in combination with various chemotherapy drugs.[35] The ClinicalTrials.gov registry lists at least 18 trials that test various PARP inhibitors, including olaparib,[52,53] talazoparib,[54] rucaparib,[55] and niraparib,[56] in breast cancer.
KEY POINTS in the Treatment of Triple-Negative Breast Cancer (TNBC)
- When possible, the use of neoadjuvant therapy is preferred for the treatment of stage II to III TNBC.
- Enrollment in a clinical trial is suggested for patients with residual disease following neoadjuvant therapy.
- Genetic testing is recommended for all women with TNBC diagnosed under the age of 60 years.
- In patients with germline BRCA mutations, referral to a clinical trial that tests the role of poly (ADP-ribose) polymerase inhibitors and/or platinum agents is suggested.
- When possible, patients should be enrolled in a clinical trial using immune checkpoint inhibitors.
- Patients with metastatic TNBC should be considered for antibody-drug conjugate trials and molecularly targeted basket studies using relevant targeted drugs.
Antiandrogens
Because only a small subset of TNBCs express ARs, patient accrual to clinical trials that explore antiandrogens as treatment for this disease has been a challenge. At least two studies have tested the activity of single-agent antiandrogen therapy, including with bicalutamide (an AR antagonist) and enzalutamide; somewhat disappointingly, both trials reported objective response rates in the single digits, although a larger fraction of patients (20% to 35%) experienced disease stabilization.[57,58] It is unclear whether these findings reflect the relatively indolent nature of AR-positive TNBC or are a sign of real but limited drug activity. Two ongoing trials continue to address the role of the antiandrogens orteronel and enzalutamide as treatment for AR-positive metastatic TNBC (ClinicalTrials.gov identifiers: NCT01990209, NCT02457910).
Histone deacetylase inhibitors
These drugs modulate gene expression through epigenetic regulation and can induce cell cycle arrest, differentiation, and apoptosis. Panobinostat is a potent pan–histone deacetylase inhibitor with preclinical activity in TNBC. A phase I/II clinical trial of panobinostat in combination with letrozole for patients with metastatic disease (ClinicalTrials.gov identifier: NCT01105312) tested the hypothesis that the drug can induce ER re-expression in TNBC cells, and this expression can then be inhibited by an aromatase inhibitor.[59] Several other histone deacetylase inhibitors are currently being tested as treatment for metastatic TNBC in combination with chemotherapy (romidepsin + cisplatin; ClinicalTrials.gov identifier: NCT02393794) or with immune checkpoint inhibitors (entinostat + ipilimumab + nivolumab; ClinicalTrials.gov identifier: NCT02453620 and entinostat + pembrolizumab; ClinicalTrials.gov identifier: NCT02909452).
Immune checkpoint inhibitors
Because of the higher levels of lymphocytic infiltration seen in TNBC compared with other breast cancer subtypes, and the favorable prognostic impact of lymphocytes, many trials are exploring various immune checkpoint inhibitors for the management of this disease.[60-62] However, the only published clinical trial results are from the KEYNOTE-012 study, which assessed pembrolizumab as single-agent therapy in programmed death ligand 1–positive metastatic TNBC (defined as ≥ 1% of stromal or tumor cells staining positive by immunohistochemistry).[38] The study showed an 18% objective response rate, with a median duration of response not yet reached because many of the responses were sustained (with 3 of 5 responders continuing treatment beyond 12 months).[38] Pembrolizumab, durvalumab, ipilimumab, nivolumab, tremelimumab, and atezolizumab are all being tested in close to 50 different ongoing clinical trials that solely target breast cancer or accept breast cancer patients.
Antibody-drug conjugates
Antibody-drug conjugates represent another promising new class of drugs in the treatment of TNBC. Motivated by the success of T-DM1 (trastuzumab conjugated to emtansine), a variety of antibody-drug conjugates are being developed against cell-surface antigens in breast cancer. The SGN-LIV1A antibody conjugated to monomethyl auristatin targets the LIV-1 antigen, a zinc transporter that is expressed in about 80% of breast cancers.[63] This drug is in phase I to II testing, and preliminary results indicate a 47% objective response rate in 17 patients with TNBC (ClinicalTrials.gov identifier: NCT01969643). CDX-011 (glembatumumab vedotin) targets the glycoprotein NMB and is also conjugated to monomethyl auristatin. A phase IIb study showed that in patients with high expression of glycoprotein NMB, treatment with CDX-011 was associated with a median overall survival of 10 months compared with 5.5 months with chemotherapy (P = .003). Fatigue, rash, nausea, peripheral sensory neuropathy, and neutropenia were the most frequent adverse events reported.[64] CDX-011 is now being compared with capecitabine monotherapy in a randomized clinical trial for patients with metastatic TNBC (ClinicalTrials.gov identifier: NCT01997333). IMMU-132 targets TROP-2, a transmembrane glycoprotein, and is conjugated to SN38, an active metabolite of irinotecan. In a phase II study (ClinicalTrials.gov identifier: NCT01631552) including patients with TNBC, this agent yielded a 30% objective response rate and median progression-free survival of 7 months.
Conclusion
After 2 decades of relatively few improvements in the management of TNBC, a number of important new trials and novel drugs have started to move the field forward. In early-stage TNBC, neoadjuvant administration of standard-of-care chemotherapy provides a potentially life-saving advantage: the opportunity to receive postoperative adjuvant chemotherapy with capecitabine, or participate in a clinical trial if there is extensive residual cancer after neoadjuvant therapy. There is growing evidence that cisplatin incorporated into a taxane/anthracycline regimen results in higher pCR rates and in particular may benefit patients with germline BRCA-mutant cancer. The adjuvant trial of olaparib for germline BRCA-mutant tumors is also an important study that should be considered for high-risk germline BRCA-mutant early-stage TNBC. Further, entirely new therapeutic modalities are emerging, such as antibody-drug conjugates and immune checkpoint inhibitors. There are nearly 50 ongoing (or soon to open) clinical investigations of the role of immune checkpoint inhibitors and other immune-targeted agents in breast cancer. In an unprecedented manner, these drugs are being developed simultaneously in phase I, II, and III trials in both the metastatic and early-stage adjuvant/neoadjuvant setting.
Financial Disclosure:Dr. Pusztai receives clinical trial research funding from AstraZeneca, Clovis Pharmaceuticals, Genentech, Merck, Novartis, and Seattle Genetics. The other authors have no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.
Acknowledgment:This work was supported in part by grants from the Breast Cancer Research Foundation and a Komen Leadership Award to Dr. Pusztai, and a Rosztoczy Foundation Scholarship to Dr. Székely.
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