The cautionary note is that while neoadjuvant studies are being used to give us a sense of how to use regimens in the future, the underlying population is key to the interpretation.
—Lisa Carey, MD
Triple-negative breast cancer—which lacks expression of the estrogen receptor, progesterone receptor, and HER2 oncogene—is a challenge for oncologists. The emergence of data showing strong heterogeneity for this subtype of breast cancer creates even more confusion regarding prognosis and management. The ASCO Post asked Lisa Carey, MD, who has led much of the research in triple-negative breast cancer, to describe what is currently known, and remains unclear, about the disease.
Dr. Carey is the Preyer Distinguished Professor in Breast Cancer Research, Medical Director of the University of North Carolina Breast Center, Division Chief of Hematology-Oncology at UNC School of Medicine, and Physician-in-Chief of the North Carolina Cancer Hospital, Chapel Hill.
Triple-negative breast cancer is now known to exist in the form of several subtypes. Can you describe these?
Molecular assays have shown that there is indeed discordance within breast cancers that we consider “triple-negative.” The main molecular subtype is basal-like (49%), which is high in proliferation genes and is genomically unstable. The second most common is the claudin-low subtype (30%), a more recently defined subset that is relatively low in proliferation genes and genetically more stable. The remainder include the HER2-enriched (9%), luminal A (5%), luminal B (6%), and normal-like (1%) subtypes.
Defining ‘Borderline’ Disease
What constitutes “borderline” triple-negative breast cancer tumors, and how are these approached clinically?
Studies define triple-negative breast cancer variably. Some say there must be zero expression of estrogen and progesterone receptors, while others have allowed up to 10% expression of these receptors. These are called “borderline” triple-negative breast cancers, and research from cooperative groups has shown that there is much diversity within these tumors. Often they are half luminal, half other types. Clinically, we should make no assumptions about them. We should treat these patients with adjuvant endocrine therapy.
How do you determine prognosis for triple-negative breast cancer tumors?
Prognosis can be accurately estimated by the usual variables. Even stage III tumors are well represented in Adjuvant! Online and other models. At 10 years, these patients have an 85% risk of relapse and a 79% risk of death without systemic therapy. With well-delivered third-generation chemotherapy regimens, however, risk can be reduced by 24%, so that their 10-year mortality risk becomes 55%.
We don’t do as well in estimating the outcome of very small tumors (T1a, N0 triple-negative breast cancer). The decision-making models come up with a 19% risk of relapse at 5 years, but you cannot rely on this. The truth is, relapse in these models includes outcomes that from a prognostic standpoint are “noise,” such as in-breast and local recurrences, as well as new primaries and true relapse. Since these tumors relapse early, the better metric for decision-making in triple-negative breast cancer is the 10-year mortality risk, which is about 8%. It is a more useful number for you and your patient in decision-making.
So, there actually are “good-prognosis” triple-negative tumors?
Untreated T1a and T1b node-negative tumors have a distant recurrence-free survival rate at 5 years of over 85%. These patients can do quite well.
There is an assumption that standard chemotherapy regimens are not effective in triple-negative breast cancer. Is this accurate?
No. Third-generation chemotherapy regimens are, in fact, effective in the majority of subsets of triple-negative breast cancer. [Third-generation regimens are typically those including anthracyclines and taxanes given either for several cycles or in a dose-dense fashion. Examples include dose-dense doxorubicin plus cyclophosphamide followed by docetaxel (AC-T) and docetaxel, doxorubicin, and cyclophosphamide (TAC).] A study of 360 patients with the disease presented at the 2011 San Antonio Breast Cancer Symposium showed pathologic complete response rates of 73% in basal-like tumors and 39% in claudin-low tumors after third-generation neoadjuvant chemotherapy.1 There are no data suggesting you should use other than conventional agents in this setting.
The cautionary note is that while neoadjuvant studies are being used to give us a sense of how to use regimens in the future, the underlying population is key to the interpretation. If a study population has mostly luminal tumors, you can expect a lower pathologic complete response rate, regardless of the drug.
Association with BRCA Mutation
What is the association between triple-negative breast cancer and the BRCA1 mutation?
Eighty percent of BRCA1-associated breast cancers are basal-like, so there is a tight association with triple-negative breast cancer. Also, there are clearly defined shared characteristics between BRCA1-associated tumors and sporadic triple-negative breast cancer, which has been labeled “BRCAness.” In addition to the propensity for the basal-like phenotype, there are other factors such as estrogen receptor and HER2 negativity, high grade, and sensitivity to DNA damage.
There are therapeutic implications of this BRCA loss, and one is that theoretically BRCA1 deficiency is targetable. This has implications for the choice of chemotherapy. If BRCA is key to repairing DNA damage, then with BRCA loss, the tumor should become hypersensitive to DNA-damaging drugs such as platinum agents. In the neoadjuvant setting, pathologic complete response rates to single-agent cisplatin in BRCA1 mutation carriers are extremely high—over 80%, according to small but biologically plausible studies.
We could exploit the DNA damage response as a mechanism of treatment itself, and this is where poly-ADP-ribose polymerase (PARP) inhibition comes in. When BRCA1 or BRCA2 is already damaged, cells become dependent on other repair types. PARP inhibitors such as olaparib exploit this Achilles’ heel. Olaparib as a single agent has been shown to produce high response rates in heavily pretreated BRCA mutation carriers.
In sporadic triple-negative breast cancer, we do not see incredible sensitivity to PARP inhibitors, but this is being further evaluated in randomized trials. At this point it appears that PARP inhibition is promising in BRCA-associated tumors, but its efficacy in sporadic triple-negative breast cancer is unclear.
Drugs Targeting Angiogenesis and EGFR
How might antiangiogenic drugs and those targeting the epidermal growth factor receptor (EGFR) work in triple-negative breast cancer?
Preclinical data have suggested that triple-negative breast cancer may be particularly susceptible to antiangiogenic approaches. The reality is that bevacizumab (Avastin) may improve progression-free survival but not overall survival. There is some reason to think, however, that the micro- and macrometastatic arenas may be different, and neoadjuvant and adjuvant trials are now addressing micrometastatic disease.
EGFR is frequently mentioned as a possible target in triple-negative breast cancer, and a randomized phase II trial that paired cetuximab (Erbitux) with cisplatin demonstrated a 20% response rate, vs 10.3% with cisplatin alone, and a doubling in progression-free survival from 1.5 to 3.1 months.2 So while there is some improvement, it is not enough. We need a selection strategy for this approach.
Treating a Heterogeneous Disease
If triple-negative breast cancer is so heterogeneous, will different approaches be needed for the various subtypes?
Acknowledging this heterogeneity in triple-negative breast cancer, we clearly will need more than one strategy. Biologically distinct groups will have multiple potential targets, such as DNA damage response genes, growth factor pathways, and the PI3K/mTOR pathway.
Androgen receptor signaling may also be a target. In a study of patients with androgen receptor–positive triple-negative breast cancer presented at this year’s ASCO Annual Meeting,3 targeting of the receptor with bicalutamide (a nonsteroidal antiandrogen used in prostate cancer) yielded a clinical benefit rate of 21% and was well tolerated. The downside was that 450 patients were screened to find 52 who expressed the androgen receptor and 26 who were eligible for the trial.
How would you summarize the current state of knowledge and practice in the treatment of triple-negative breast cancer?
What we know for sure is that triple-negative breast cancer is a heterogeneous tumor and adjuvant chemotherapy works the same in these tumors as for other subtypes of breast cancer. You have the same treatment options as for other breast cancers, and you should make similar choices.
What we would like to learn is how to identify BRCA-like tumors, or “BRCAness.” Outside of germline mutations, we don’t have much information. Triple-negative breast cancer is where we really need a “genome-forward” approach—ie, a means of identifying the molecular makeup of an individual tumor to guide therapy. The alignment of tissue-based and clinical trials will be key to our success. ■
Disclosure: Dr. Carey reported no potential conflicts of interest.
1. Prat A, Perou CM: Deconstructing the molecular portraits of breast cancer. Mol Oncol 5:5-23, 2011.
2. Baselga J, Gomez P, Awada A, et al: The addition of cetuximab to cisplatin increases overall response rate and progression-free survival in metastatic triple-negative breast cancer: Results of a randomized phase II study (BALI-1). 2010 ESMO Congress. Abstract 2740. Presented October 11, 2010.
3. Gucalp A, Tolaney SM, Isakoff SJ, et al: Targeting the androgen receptor in women with AR+ ER-/PR- metastatic breast cancer. 2012 ASCO Annual Meeting. Abstract 1006. Presented June 5, 2012.
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