Triple-Negative Breast Cancer: 2018 Status Update

Editor's Notes

• #2: Abbreviations: AR, androgen receptor; BRCA, breast cancer (susceptibility genes); ER, estrogen receptor; HER2, human epidermal growth factor receptor-2; PD-L1, programmed death-ligand 1; TIL, tumor infiltrating lymphocytes; TNBCs, triple-negative breast cancers Notes: Up to 20% of all invasive female breast cancer diagnoses are defined by the clinically significant absence of three hormone receptors i.e., ER, PR and HER2. This group of highly heterogeneous tumors exhibit aggressive growth patterns and are known as TNBCs. Although most TNBCs are ductal carcinomas (no special types), the identification of specific histologic/molecular subtypes potentially open up further modes of treatment for a disease that has thus far mainly been treated with cytotoxic chemotherapies. Biologic features in tumor subsets that carry such implications include BRCA pathway inhibition, increased tumor infiltrating lymphocytes (TILs), detection of other biomarkers paving the way for immunotherapies such as elevated PD-L1 expression and AR expression. Here, is some of the relevant information about TNBCs. Reference: 1. Tan AR. Triple-Negative Breast Cancer: A Clinician's Guide: Springer; 2018.
• #3: Notes: ~ 1 in 8 American women will develop breast cancer (BC) [1] Most women respond to treatment Relative 5-year survival rates = 89.7%[2] Treatment protocols for breast cancer depend predominantly on receptor status with respect to ER, PR and HER2 [3] Endocrine responsiveness and molecular subtypes are often predictive of outcomes TNBC is one subtype associated with a poorer prognosis4 Presents aggressively with rapid growth, and are more likely to be diagnosed clinically rather than mammographically or as interval cancers between mammograms [4] Some researchers have proposed that TNBC can be further sub-classified as either AR+ TNBC or quadruple negative (AR-ER-PR-HER2-) breast cancer, since targeting AR may represent a viable therapeutic option for a subset of TNBC.[5] See next slide References: American Cancer Society. How common is breast cancer? 2018; https://www.cancer.org/cancer/breast-cancer/about/how-common-is-breast-cancer.html. Accessed February, 2018. National Cancer Institute. Surveillance, Epidemiology, and End Results Program. Cancer Stat Facts: Female Breast Cancer. 2018; https://seer.cancer.gov/statfacts/html/breast.html. Accessed February, 2018. Hon JD, Singh B, Sahin A, et al. Breast cancer molecular subtypes: from TNBC to QNBC. Am J Cancer Res. 2016;6(9):1864-1872. Anders CK, Abramson V, Tan T, Dent R. The Evolution of Triple-Negative Breast Cancer: From Biology to Novel Therapeutics. Am Soc Clin Oncol Educ Book. 2016;35:34-42. Barton VN, D'Amato NC, Gordon MA, Christenson JL, Elias A, Richer JK. Androgen Receptor Biology in Triple Negative Breast Cancer: a Case for Classification as AR+ or Quadruple Negative Disease. Horm Cancer. 2015;6(5-6):206-213.
• #4: Abbrevation: y, years old Notes: Older women [1] ~10% of women over the age of 65 was also diagnosed with TNBC in one study Several studies suggest wide variability and breadth of clonal spectra in TNBC The basal TNBC subtype is molecularly defined by a “basal cluster” of genes [2] Includes 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 Two two basal-like subtypes (BL1 and BL2) have also been identified Additional subtypes include immunomodulatory, mesenchymal, mesenchymal stem-like, , claudin-low and interferon-rich, as well as luminal androgen (LAR) subtypes The LAR subtype is of particular interest as AR is expressed in almost half of all TNBCs [3] AR expression has been associated with a more favorable prognosis and prolonged survival in other endocrine responsive BCs Similarly, AR+TNBC may potentially be more amenable to non-chemotherapeutic regimens than quadruple negative TNBC (AR-HER2-ER-PR-) Mutations in p53 or several DNA repair genes e.g., especially the BRCA genes, or the aberrant expression of these genes may impact chemosensitivity to platinum or the action of targeted therapies5 References: Shachar SS, Jolly TA, Jones E, Muss HB. Management of Triple-Negative Breast Cancer in Older Patients: How Is It Different? Oncology (Williston Park). 2018;32(2):58-63. Anders CK, Carey LA. Epidemiology, risk factors, and the clinical approach to ER/PR negative, HER2-negative (Triple-negative) breast cancer. 2017; https://www.uptodate.com/contents/epidemiology-risk-factors-and-the-clinical-approach-to-er-pr-negative-her2-negative-triple-negative-breast-cancer?search=triple%20negative%20breast%20cancer&source=search_result&selectedTitle=1~26&usage_type=default&display_rank=1#H267308777 Christenson JL, Trepel JB, Ali HY, et al. Harnessing a Different Dependency: How to Identify and Target Androgen Receptor-Positive Versus Quadruple-Negative Breast Cancer. Horm Cancer. 2018.
• #5: Abbreviations: ID, identificaion; IHC, immunohistochemistry; PFS, progression-free survival; TNM = tumor, node, metastasis Notes: Diagnosis of triple-negative breast cancer mirrors that of other breast cancer subtypes and requires testing for ER, PR, and HER2[1] Lack of a receptor defined as <1% staining by IHC Like other BCs, the TNM system is also used to stage TNBCs neoadjuvant therapy for patients with breast cancer, with special considerations for those with triple-negative breast cancer including the incorporation of platinum agents4 Surgical management, radiation therapy, neoadjuvant and adjuvant chemotherapeutic options are also similar to other BCs[1] Neoadjuvant therapy for patients with breast cancer, with special considerations for those with TNBC include the incorporation of platinum-based agents Use of adjuvant chemotherapy is controversial for patients with residual disease who initially completed neoadjuvant chemotherapy As many as 50% of patients diagnosed with early-stage triple-negative breast cancer (stages I to III) experience disease recurrence [2] 37% die in the first 5 years after surgery Similarly, patients with metastatic triple-negative breast cancer have short PFS after failure of first-line chemotherapy (median PFS, 3 to 4months) [2] Metastatic disease is characterized by higher relapse rates compared with estrogen receptor (ER)-positive breast cancers, including an increased risk of locoregional recurrence, lung, and brain involvement [2] Risk of distant recurrence and death reaches a peak at ~ 3 years after diagnosis and declines after that time In patients with metastatic breast cancer, a confirmatory biopsy of a suspected lesion should be obtained when possible with reassessment of ER, progesterone receptor (PR), and HER2, because of possible differences of these markers between primary and metastatic disease With the exception of BRCA mutation carriers, in whom response rates and progression-free survival is superior with first-line platinum versus taxane treatment, there is no evidence to support a preference for any one chemotherapy agent or combination for initial therapy of metastatic triple-negative breast cancer References: Anders CK, Abramson V, Tan T, Dent R. The Evolution of Triple-Negative Breast Cancer: From Biology to Novel Therapeutics. Am Soc Clin Oncol Educ Book. 2016;35:34-42. Costa RLB, Gradishar WJ. Triple-Negative Breast Cancer: Current Practice and Future Directions. J Oncol Pract. 2017;13(5):301-303.
• #6: Reference: Shachar SS, Jolly TA, Jones E, Muss HB. Management of Triple-Negative Breast Cancer in Older Patients: How Is It Different? Oncology (Williston Park). 2018;32(2):58-63.
• #7: Key abbreviations: pCR, pathologic complete response; PARP, poly(ADP)ribose polymerase; OS, overall survival Notes: Epithelial growth factor receptor inhibitors [1] The epidermal growth factor receptor (EGFR/HER1) is perhaps the most well-known protein overexpressed among TNBCs for which several monoclonal antibodies and small-molecule inhibitors exist Angiogenesis inhibitors [1] No evidence thus far that these agents impact OS in TNBC PARP inhibitors Inhibitors of poly (adenosine diphosphate-ribose) polymerase (PARP) are another class of agents that may be particularly useful in BRCA-mutated breast cancer, of which most are triple-negative. For patients with germline BRCA mutations and HER2-negative breast cancer, olaparib has shown efficacy Immunotherapy TNBC is more immunogenic than other BCs and may have a more robust response Initial single-agent responses in PD-L1-positive, triple-negative breast cancer are approximately 20 percent for both PD-1 and PD-L1 antibodies Additional strategies, including combination immunotherapy with chemotherapy and preoperative immunotherapy approaches, are in development Optimization of biomarkers predictive of response to immunotherapy are actively under investigation Other agents/approaches Other therapies for TNBC that target other pathways and cognate molecules such as AKT, MEK, and PI3K-mTOR pathways are under development (NCT01964924, NCT02423603, and NCT02208375). Early results of the I-SPY 2 (Neoadjuvant and Personalized Adaptive Novel Agents to Treat Breast Cancer) trial, which used adaptive randomization of only 106 patients to neoadjuvant treatment with a paclitaxel-carboplatin-veliparib combination or to paclitaxel alone. This trial showed that treatment with the combination correlated with higher pCR rates (51% v 26%) Multiple histology basket trials that enroll patients with triplenegative breast cancer whoharbor rare genomic aberrations (ie, mutations in HER2, EGFR,and HER3) are ongoing and represent another way forward (NCT01953926). References: Anders CK, Abramson V, Tan T, Dent R. The Evolution of Triple-Negative Breast Cancer: From Biology to Novel Therapeutics. Am Soc Clin Oncol Educ Book. 2016;35:34-42. Costa RLB, Gradishar WJ. Triple-Negative Breast Cancer: Current Practice and Future Directions. J Oncol Pract. 2017;13(5):301-303