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Treating Triple-Negative Breast Cancer: Where Are We?

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Treating Triple-Negative Breast Cancer: Where Are We? e8 Review Treating Triple-Negative Breast Cancer: Where Are We? Aki Morikawa, MD, PhD, and Andrew D. Seidman, MD Abstract and rare types, such as adenoid cystic, metaplastic, apo- Unlike estrogen receptor (ER)–positive and HER2-positive breast can- crine, and neuroendocrine carcinoma.3 Nevertheless, cer, triple-negative breast cancer (TNBC) lacks a repertoire of targeted therapies. Hence, chemotherapy is the only available systemic option the clinical utility of this categorization has been robust in current clinical practice. In general, survival of patients with TNBC as a prognostic and predictive biomarker. is worse than that for those with ER-positive and HER2-positive breast Patients with TNBC are more likely to have a cancer, especially for advanced-stage disease. Thus, a great unmet poor prognosis than those with estrogen receptor (ER)/ need exists. Conventional chemotherapeutic agents such as platinum- progesterone receptor (PR)–positive and/or HER2-pos- salts have been examined for specific benefit in TNBC; however, no itive breast cancer.4 This is likely partially attributable one agent has yet been shown to offer a differential incremental benefit in metastatic TNBC. The hope is that ongoing research in tar- to a dearth of novel therapeutic options for TNBC, in getable molecular pathways will lead to new therapeutic options for contrast to the recent expansion of endocrine and anti- TNBC. Because these patients are likely to be increasingly subcatego- HER2 therapies (eg, ado-trastuzumab-emtansine, per- rized using potentially targetable molecular alterations, investigators tuzumab, everolimus with exemestane).5–7 Therefore, will need to be mindful of the challenges in designing and conduct- great interest has been shown in exploring potential ing clinical trials in smaller subpopulations. The successful incorpora- tion of targeted therapies in routine clinical practice for TNBC, which biomarkers (prognostic and predictive) and developing mirrors the success achieved by anti-HER2 and endocrine therapies, is new therapeutic options. This article reviews current awaited. (J Natl Compr Canc Netw 2015;13:(e8–e18) treatment options (“where are we now?”) and ongoing therapeutic research (“where are we going?”) for TNBC. Contemporary systemic therapy is commonly informed by the classification of breast cancer based solely on hor- Heterogeneity of TNBC monal receptor and HER2 status. Triple-negative is a Because the utilitarian definition of TNBC is simply category of exclusion defined by immunohistochemical based on the exclusion of ER/PR/HER2 expression, it is and/or fluorescence in situ hybridization–based criteria, not unexpected that this clinical subtype remains bio- which has undergone modification over time (ASCO/ logically heterogeneous. Studies examining tumor char- CAP guidelines).1,2 Histologically, triple-negative breast acteristics have found correlations between TNBC and cancer (TNBC) is a heterogeneous group of breast can- certain molecular genomic features, such as basal cyto- cers that includes common infiltrating ductal carcinoma keratin (eg, CK5/6) and epidermal growth factor recep- tor (EGFR) expression, checkpoint kinase (Chk1), p53 From Breast Medicine Service, Memorial Sloan Kettering Cancer alterations, and BRCA1 germline mutations.8–13 TNBC Center, New York, New York. Submitted April 20, 2014; accepted for publication August 6, 2014. has also been shown to have overlapping features with Dr. Morikawa has received research support from the Susan G. the basal-like subtype (intrinsic breast cancer classifi- Komen Foundation and the ASCO Conquer Cancer Foundation 14,15 Bonadonna Fellowship. Dr. Seidman has served as a consultant for cation), including a high frequency of poorly differ- Genentech/Roche and Pfizer and has received payment for lectures, entiated tumors, expression of cytokeratins and EGFR, including service on speaker bureaus from Genentech, Genomic Health, Eisai, and Celgene, and research support from the Susan G. and p53 mutations. Although the basal-like–subtypes Komen Foundation. Correspondence: Andrew D. Seidman, MD, Evelyn H. Lauder Breast are most often triple-negative, they are not equivalent Center, Memorial Sloan Kettering Cancer Center, 300 East 66th groups.16,17 In a gene expression study of 579 TNBCs, Street, New York, NY 10065. E-mail: [email protected] 73% of TNBCs showed basal-like characteristics.18 © JNCCN—Journal of the National Comprehensive Cancer Network | Volume 13 Number 2 | February 2015 Review e9 Treating Triple-Negative Breast Cancer The Cancer Genome Atlas (TCGA) project antitumor activity in TNBC compared with non- reporting of breast cancer molecular analysis also TNBC. Thus, certain classes of chemotherapeutic showed significant overlap between TNBC and bas- agents have been preferentially evaluated in patients al-like features and similarity to high-grade serous with TNBC. ovarian cancer.19 The TCGA basal-like subanalysis Microtubule-Targeting Agents and the primary TNBC analysis identified several in- Based on the TNBC subtypes, the basal-like types volved pathways that included PTEN, PI3K/PTEN, are postulated to respond well to taxanes because cell cycle, and growth factors, and highlighted the of their expression of proliferation genes.21 Efficacy heterogeneity of TNBC.19,20 Recently a large meta- of paclitaxel specifically for TNBC (compared with analysis of 587 TNBC gene expression profiles from non-TNBC) has been observed in subtype analyses 21 data sets described 7 TNBC subtypes with 6 po- within clinical trials.24,25 However, these associations tentially targetable pathways.21 Those subtypes con- between TNBC and taxanes have not been consis- sist of 2 basal-like types (BL1 and BL2), immuno- tent; a meta-analysis has shown benefit for taxane in modulatory (IM), mesenchymal (M), mesenchymal the adjuvant setting independent of ER status.26 stem-like (MSL), luminal androgen receptor (LAR), Ixabepilone is an epothilone B analogue that and unstable (UNS). The BL1 subtype was charac- stabilizes microtubules and has activity in patients terized by cell cycle/cell division and DNA damage with TNBC as a monotherapy.27 In a phase III study response pathways (and association with the BRCA of ixabepilone and capecitabine versus capecitabine, deficiency). The BL2 subtype was typified by growth improvements in response rate and median progres- factor signaling such as via the EGFR pathway. The sion-free survival (PFS) were noted for the combi- IM subtype was named for a cluster that contained nation regimen in the TNBC subset compared with immune-related processes. The M and MSL types the ER-positive subset (response rate, 27% vs 9%, were both associated with motility and epithelial to and median PFS, 4.1 vs 2.1 months, respectively).28 mesenchymal transition (EMT), but the MSL had However, no significant benefit was noted in terms more stem cell–like features. The LAR subtype con- of median OS for patients with TNBC (hazard ratio tained the genes involved in androgen and steroid [HR], 0.83; P<.05).29 pathways. In addition, various cell lines were clas- Eribulin is a halichondrin B analogue that per- sified into these TNBC subtypes and evaluated for turbs microtubule dynamics. It demonstrated a sur- responses to therapy designed to match to the ap- vival benefit in heavily pretreated metastatic breast propriate representative subtype.21 A Web-based cancer (MBC) compared with the treatment of phy- subtyping tool was also created that allowed normal- sician’s choice in the EMBRACE trial.30 The phase ized gene expression data to be analyzed for TNBC III “301” trial compared eribulin with capecitabine subtypes.22 in 1102 pretreated patients with MBC, and reported a significant improvement in median OS associ- Treating TNBC: Where Are We Now? ated with eribulin among the subset of patients with TNBC in an exploratory analysis (14.4 vs 9.4 mo; Currently, cytotoxic chemotherapy is the standard HR, 0.7; P=.01).31 However, in the published ver- therapeutic approach for TNBC. TNBC is relatively sion of this study, the authors did not report any sig- chemosensitive, as evidenced by relatively higher nificant difference in benefit among the subgroups.32 pathologic complete response (pCR) rates compared Given that patients with metastatic TNBC often with other subtypes, such as ER-positive/HER2-neg- require multiple lines of chemotherapy, eribulin and ative.23 This may be explained partially by the fact that TNBC is often associated with a high grade and capecitabine are both likely to remain useful. Eribu- proliferative rate. However, despite higher response lin is also being evaluated in combination with car- boplatin (neoadjuvant) and everolimus (metastatic) rates, they have an inferior outcome with respect to 33,34 time to recurrence and overall survival (OS) after for the treatment of for TNBC. chemotherapy.4 Preclinical studies and subgroup Platinum Salts analyses within clinical trials have suggested that TNBCs have been associated with BRCA mutation certain chemotherapeutic agents have differential status. BRCA-mutated tumors have defects in their © JNCCN—Journal of the National Comprehensive Cancer Network | Volume 13 Number 2 | February 2015 e10 Review Morikawa and Seidman homologous recombination repair mechanism and carboplatin showed differential benefit compared are thought to be particularly vulnerable to DNA- with docetaxel (response rate, 68.0% vs 33.3% for damaging agents.35 In addition to the association of patients with BRCA mutations and 28.1% vs
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