ONCOLOGY.
No. 11
NATIONAL BREAST CANCER AWARENESS MONTH
Understanding and Treating Triple-Negative Breast Cancer
By CAREY ANDERS, MD
Assistant Professor
LISA A. CAREY, MD
Associate Professor
Hematology-Oncology
University of North Carolina at Chapel Hill
Chapel Hill, North Carolina
|
September 30, 2008
Financial Disclosure: The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.
This article is part of a CME activity described in Oncology Vol. 22 No. 11
More recently, scientific efforts aimed at dissecting the biology of triple-negative breast cancer have revealed several promising targeted strategies including EGFR-targeted agents, antiangiogenic agents, and PARP inhibitors. • EGFR Inhibitors—As mentioned previously, EGFR expression is seen in approximately 60% of triple-negative breast tumors, thus providing a rational, targeted treatment approach.[10] Cetuximab(Drug information on cetuximab) (Erbitux) a chimeric monoclonal antibody targeting EGFR, elicits little response to single-agent therapy in the setting of advanced triple-negative breast cancer.[50] However, a phase II trial evaluating the combination of cetuximab and carboplatin(Drug information on carboplatin) (area under the concentration-time curve [AUC]2, weekly for 3 of 4 weeks) reported a response rate of 18% and overall clinical benefit rate of 27% among 102 patients with advanced pretreated triple-negative breast cancer. Time to progression was 2 months, and overall survival was 12 months, which reflects the aggressive nature of this disease.[55] A second study evaluating the combination of irinotecan and carboplatin with or without cetuximab reported response rates of 49% and 30%, respectively, among 72 patients with pretreated triple-negative breast cancer. The incidence of toxicity, including grade 3/4 fatigue, diarrhea, vomiting, neutropenia, and thrombocytopenia, was higher among patients who received cetuximab.[52] • PARP Inhibitors—PARP1, a gene that encodes a chromatin-associated enzyme that modifies various nuclear proteins, is involved in the molecular events leading to cell recovery from DNA damage. When PARP1 is inhibited, double-strand DNA breaks accumulate that under normal conditions would be repaired via homologous recombination. Both BRCA1 and BRCA2 are required for the homologous recombination pathway to function properly. Therefore, cells deficient in either BRCA1 or BRCA2 are exquisitely sensitive to PARP1 inhibition, resulting in cell death/apoptosis.[56,57] Inhibition of the PARP pathway has become an attractive research question for patients with BRCA-associated malignancies. Several PARP1 inhibitors (ie, AZD2281, BSI-201) are currently in clinical development and hold promise in this unique setting.[1,58,59] • Antiangiogenic Agents—The antiangiogenic agent bevacizumab (Avastin), a monoclonal antibody targeting all forms of vascular endothelial growth factor (VEGF)-A, is active in a variety of solid tumors including breast cancer. The landmark study E2100 illustrated improvement in progression-free survival (11.8 vs 5.9 months, HR = 0.60, P < .001) when adding bevacizumab to paclitaxel(Drug information on paclitaxel) chemotherapy compared with single-agent paclitaxel alone in first-line treatment of metastatic disease. Subset analyses indicated that the treatment effect persisted among ER/PR–negative patients (HR = 0.53, 95% confidence interval = 0.40–0.70) in this largely (> 90%) HER2-negative patient population.[60] Additionally, small-molecule inhibitors of the VEGF pathway appear to have activity in the subset of pretreated triple-negative breast cancer; definitive studies are underway.[61,62] Several contemporary studies are examining antiangiogenic strategies alone or in tandem with other investigational approaches in triple-negative breast cancer. CALGB 40603, for example, is a neoadjuvant study examining the benefit of carboplatin added to paclitaxel and the benefit of bevacizumab added to primary chemotherapy. Echoing the oft-noted need for better tissue correlates in targeted therapy trials, this is a clinical trial with correlative science studies embedded; pretherapy research biopsies are mandatory. This trial, which is expected to open to accrual in the fall of 2008, will not only help answer two specific clinical questions in triple-negative breast cancer—the role of platinum agents and the role of antiangiogenics—but in addition, it will provide crucial data regarding response and resistance patterns within this subtype. In summary, triple-negative breast cancer largely represents a subtype of breast tumors with unique molecular and clinical characteristics, distinctive risk factors and patterns of recurrence, association with BRCA1 mutation status, inferior prognosis, and expanding therapeutic options. Multiple excellent approaches to improved care of triple-negative breast cancer, including DNA-damaging agents such as platinums, targeted agents against EGFR and VEGF, and PARP inhibitors are under investigation. Current research strategies are aimed at better understanding both the risk factors and the biology underlying triple-negative breast cancer, with the goal of developing preventive measures and improving treatment strategies for this challenging subtype of breast cancer. This article is reviewed here: Triple-Receptor–Negative Breast Cancer: What We Know and Issues to Be Resolved
Triple Negative Breast Cancer
References
1. Swain S: Triple-negative breast cancer: Metastatic risk and role of platinum agents. Presented at the Annual Meeting of the American Society for Clinical Oncology; Clinical Science Symposium; Chicago; June 3, 2008.
2. Perou CM, Sorlie T, Eisen MB, et al: Molecular portraits of human breast tumours. Nature 406:747-752, 2000.
3. Sorlie T, Perou C, Tibshirani R, et al: Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci U S A 98:10869-10874, 2001.
4. Sorlie T, Tibshirani R, Parker J, et al: Repeated observation of breast tumor subtypes in independent gene expression data sets. Proc Natl Acad Sci U S A 100:8418-8423, 2003.
5. Heitz F, Harter P, Traut A, et al: Cerebral metastases (CM) in breast cancer (BC) with focus on triple-negative tumors (abstract 1010). J Clin Oncol 26(15S):43s, 2008.
6. Liedtke C, Mazouni C, Hess K, et al: Response to neoadjuvant therapy and long-term survival in patients with triple-negative breast cancer. J Clin Oncol 26:1275-1281, 2008.
7. Bertucci F, Finetti P, Cervera N, et al: How basal are triple-negative breast cancers? . Int J Cancer 123:236-240, 2008.
8. Cleator S, Heller W, Coombes R: Triple-negative breast cancer: Therapeutic options. Lancet Oncol 3:235-244, 2007.
9. Kreike B, van Kouwenhove M, Horlings H, et al: Gene expression profiling and histopathological characterization of triple-negative/basal-like breast carcinomas. Breast Cancer 9:R65, 2007.
10. Nielsen T, Hsu F, Jensen K, et al: Immunohistochemical and clinical characterization of the basal-like subtype of invasive breast carcinoma. Clin Cancer Res 10:5367-5374, 2004.
11. Böcker W, Bier B, Freytag G, et al: An immunohistochemical study of the breast using antibodies to basal and luminal keratins, alpha-smooth muscle actin, vimentin, collagen IV and laminin. Part I: Normal breast and benign proliferative lesions. Virchows Arch A Pathol Anat Histopathol 421:315-322, 1992.
12. Gottlieb C, Raju U, Greenwald K: Myoepithelial cells in the differential diagnosis of complex benign and malignant breast lesions: An immunohistochemical study. Mod Pathol 3:135-140, 1990.
13. Lazard D, Sastre X, Frid M, et al: Expression of smooth muscle-specific proteins in myoepithelium and stromal myofibroblasts of normal and malignant human breast tissue. Proc Natl Acad Sci U S A 90:999-1003, 1993.
14. Nakano S, Iyama K, Ogawa M, et al: Differential tissular expression and localization of type IV collagen alpha1(IV), alpha2(IV), alpha5(IV), and alpha6(IV) chains and their mRNA in normal breast and in benign and malignant breast tumors. Lab Invest 79:281-292, 1999.
15. Nayar R, Breland C, Bedrossian U, et al: Immunoreactivity of ductal cells with putative myoepithelial markers: A potential pitfall in breast carcinoma. Ann Diagn Pathol 3:165-173, 1999.
16. Rudland P: Histochemical organization and cellular composition of ductal buds in developing human breast: Evidence of cytochemical intermediates between epithelial and myoepithelial cells. J Histochem Cytochem 39:1471-1484, 1991.
17. Rakha EA, Reis-Filho JS, Ellis IO: Basal-like breast cancer: A critical review. J Clin Oncol 26:2568-2581, 2008.
18. Korsching E, Packeisen J, Agelopoulos K, et al: Cytogenetic alterations and cytokeratin expression patterns in breast cancer: Integrating a new model of breast differentiation into cytogenetic pathways of breast carcinogenesis. Lab Invest 82:1525-1533, 2002.
19. Troester M, Herschkowitz J, Oh D, et al: Gene expression patterns associated with p53 status in breast cancer. BMC Cancer 6:276, 2006.
20. Arnes JB, Brunet JS, Stefansson I, et al: Placental cadherin and the basal epithelial phenotype of BRCA1-related breast cancer. Clin Cancer Res 11:4003-4011, 2005.
21. Foulkes W, Stefansson I, Chappuis P, et al: Germline BRCA1 mutations and a basal epithelial phenotype in breast cancer. J Natl Cancer Inst 95:1482-1485, 2003.
22. James C, Quinn J, Mullan P, et al: BRCA1, a potential predictive biomarker in the treatment of breast cancer. Oncologist 12:142-150, 2007.
23. Laakso M, Loman N, Borg A, et al: Cytokeratin 5/14-positive breast cancer: True basal phenotype confined to brca1 tumors. Mod Pathol 18:1321-1328, 2005.
24. Lakhani S, Reis-Filho J, Fulford L, et al: Prediction of BRCA1 status in patients with breast cancer using estrogen receptor and basal phenotype. Clin Cancer Res 11:5175-5180, 2005.
25. Kennedy R, Quinn J, Mullan P, et al: The role of BRCA1 in the cellular response to chemotherapy. J Natl Cancer Inst 96:1659-1668, 2004.
26. Breast Cancer Linkage Consortium: Pathology of familial breast cancer: Differences between breast cancers in carriers of BRCA1 and BRCA2 mutations and sporadic cases. Lancet 349:1505-1510, 1997.
27. Carey L, Perou C, Livasy C, et al: Race, breast cancer subtypes, and survival in the carolina breast cancer study. JAMA 295:2492-2502, 2006.
28. Dent R TM, Pritchard KI, Hanna WM, et al: Triple-negative breast cancer: Clinical features and patterns of recurrence. Clin Cancer Res 13:4429-4434, 2007.
29. Livasy C, Karaca G, Nanda R, et al: Phenotypic evaluation of the basal-like subtype of invasive breast carcinoma. Mod Pathol 19:264-271, 2006.
30. Reis-Filho J, Milanezi F, Steele D, et al: Metaplastic breast carcinomas are basal-like tumours. Histopathology 49:10-21, 2006.
31. Bauer K, Brown M, Cress R, et al: Descriptive analysis of estrogen receptor (ER)-negative, progesterone receptor (PR)-negative, and HER2-negative invasive breast cancer, the so-called triple-negative phenotype: A population-based study from the california cancer registry. Cancer 109:1721-1728, 2007.
32. Morris G, Naidu S, Topham A, et al: Differences in breast carcinoma characteristics in newly diagnosed African-American and Caucasian patients: A single-institution compilation compared with the National Cancer Institute’s Surveillance, Epidemiology, and End Results database. Cancer 110:876-884, 2007.
33. Millikan RC, Newman B, Tse C-K, et al: Epidemiology of basal-like breast cancer. Breast Cancer Res Treat 109:123-139, 2008.
34. Yang X, Sherman M, Rimm D, et al: Differences in risk factors for breast cancer molecular subtypes in a population-based study. Cancer Epidemiol Biomarkers Prev 16:439-443, 2007.
35. Fan C, Oh D, Wessels L, et al: Concordance among gene-expression-based predictors for breast cancer. N Engl J Med 355:560-569, 2006.
36. Smid M, Wang Y, Zhang Y, et al: Subtypes of breast cancer show preferential site of relapse. Cancer Res 68:3108-3114, 2008.
37. Boogerd W, Vos V, Hart A, et al: Brain metastases in breast cancer; natural history, prognostic factors and outcome. J Neurooncol 15:165-174, 1993.
38. Lin N, Bellon J, Winer E: CNS metastases in breast cancer. J Clin Oncol 22:3608-3617, 2004.
39. Bendell J, Domshek S, Burstein H, et al: Central nervous system metastasis in women who receive trastuzumab-based therapy for metastatic breast carcinoma. Cancer 97:2972-2977, 2003.
40. Lin N, Carey L, Liu M, et al: Phase II trial of lapatinib for brain metastases in patients with human epidermal growth factor receptor 2-positive breast cancer. J Clin Oncol 26:1993-1999, 2008.
41. Niwinska A, Murawska M: Brain metastases in breast cancer patients: Differences in survival depending on biological subtype and RPA RTOG prognostic class (abstract 1056). J Clin Oncol 26(15S): 55s, 2008.
42. Duchnowska R, Jassem J, Thorat MA, et al: Gene expression analysis for prediction of early brain metastasis (BM) in HER2-positive (HER2+) breast cancer patients (pts) (abstract 1019). J Clin Oncol 26(15S):45s, 2008.
43. Ibrahim NK, Abdulkarim B, Huguet F, et al: A nomogram to predict subsequent brain metastasis in metastatic breast cancer (MBC) patients (abstract 1040). J Clin Oncol 26(15S):51s, 2008.
44. Tham Y, Creighton C, Gutierrez C, et al: A gene expression signature of eventual brain metastases in patients with breast cancer (abstract 1019). J Clin Oncol 25(18S):36s, 2007.
45. Hayes N, Thor A, Dressler L, et al: HER2 and response to paclitaxel in node-positive breast cancer. N Engl J Med 357:1496-1506, 2007.
46. Carey L, Dees E, Sawyer L, et al: The triple negative paradox: Primary tumor chemosensitivity of breast cancer subtypes. Clin Cancer Res 13:2329-2334, 2007.
47. Rouzier R, Perou C, Symmans W, et al: Breast cancer molecular subtypes respond differently to preoperative chemotherapy. Clin Cancer Res 11:5678-5685, 2005.
48. Taniguchi T, Tischkowitz M, Ameziane N, et al: Disruption of the Fanconi anemia-BRCA pathway in cisplatin-sensitive ovarian tumors. Nat Med 9:568-574, 2003.
49. Turner N, Tutt A, Ashworth A: Hallmarks of ‘BRCAness’ in sporadic cancers. Nat Rev Cancer 4:814-819, 2004.
50. Carey L, Mayer E, Marcom P, et al: TBCRC 001: EGFR inhibition with cetuximab in metastatic triple negative (basal-like) breast cancer (abstract 307). Breast Cancer Res Treat 106(suppl 1):S32, 2007.
51. Garber J, Richardson A, Harris L, et al: Neo-adjuvant cisplatin (CDDP) in triple-negative breast cancer (BC) (abstract 3074). Breast Cancer Res Treat 100(suppl 1), 2006.
52. O’Shaughnessy J, Weckstein D, Vukelja S, et al: Preliminary results of a randomized phase ii study of weekly irinotecan/carboplatin with or without cetuximab in patients with metastatic breast cancer (abstract 308). Breast Cancer Res Treat 106(suppl 1):S32, 2007.
53. Sirohi B, Arnedos M, Popat S, et al: Platinum-based chemotherapy in triple-negative breast cancer. Ann Oncol June 20, 2008 (epub ahead of print).
54. Yi S, Uhm J, Cho E, et al: Clinical outcomes of metastatic breast cancer patients with triple-negative phenotype who received platinum-containing chemotherapy (abstract 1008). J Clin Oncol 26(15S):43s, 2008.
55. Carey LA, Rugo HS, Marcom PK, et al, for the Translational Breast Cancer Research Consortium: TBCRC 001: EGFR inhibition with cetuximab added to carboplatin in metastatic triple-negative (basal-like) breast cancer (abstract 1009). J Clin Oncol 26(15S):43s, 2008.
56. Bryant H, Schultz N, Thomas H, et al: Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature 434:913-917, 2005.
57. Farmer H, McCabe N, Lord CJ, et al: Targeting the DNA repair defect in brca mutant cells as a therapeutic strategy. Nature 434:917–921, 2005.
58. Fong PC, Boss DS, Carden CP, et al: AZD2281 (KU-0059436), a PARP (poly ADP-ribose polymerase) inhibitor with single agent anticancer activity in patients with BRCA deficient ovarian cancer: Results from a phase I study (abstract 5510). J Clin Oncol 26(15S):295s, 2008.
59. Kopetz S, Mita MM, Mok I, et al: First in human phase I study of BSI-201, a small molecule inhibitor of poly ADP-ribose polymerase (PARP) in subjects with advanced solid tumors (abstract 3577). J Clin Oncol 26(15S):172s, 2008.
60. Miller K, Wang M, Gralow J, et al: Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N Engl J Med 357:2666-2676, 2007.
61. Abrams T, Murray L, Pesenti E, et al: Preclinical evaluation of the tyrosine kinase inhibitor su11248 as a single agent and in combination with “standard of care” therapeutic agents for the treatment of breast cancer. Mol Cancer Ther 2:1011-1021, 2003.
62. Burstein H, Elias A, Rugo H, et al: Phase II study of sunitinib malate, an oral multitargeted tyrosine kinase inhibitor, in patients with metastatic breast cancer previously treated with an anthracycline and a taxane. J Clin Oncol 26:1810-1816, 2008.
|
|
|
Cancer Types
|
|
|
|
|
|
Supportive Care
|
More Topics
|
|
|
|
All Topics 
Five Steps to Improving Patient Access Judy Capko, May 21, 2013 Patient access is getting increased attention through reform initiatives. Here are five steps you can take to make sure patients get appropriate access to care in your office.
SearchMedica Search Result
Find peer-reviewed literature and websites for practicing medical professionals
|
