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.
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. 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. 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. 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).
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. 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. 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. 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. 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. 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. 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. The BRCA mutation status is increasingly therapeutically relevant beyond consideration of prophylactic mastectomy/oophorectomy and surveillance. 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 and Sharma.
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. Due to logistical reasons, referral patterns, and patient preferences, the adjuvant use of chemotherapy remained predominant in routine practice. 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. 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. 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. 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. 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%.
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. 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.
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