Triple–Receptor-Negative Breast Cancer: What We Know and Issues to Be Resolved

Carcinomas arising from the breast represent a heterogeneous group of tumors of distinct biologic subtypes that have been shown to be diverse in terms of response to therapy and prognostic outcomes. In an effort to understand this disease, further research has focused on characterizing breast tumor subtypes of known poor prognostic outcomes in order to define optimal therapeutic strategies to improve patient survival. Through gene-expression profiling, molecular subtypes of breast carcinomas have been identified (luminal, HER2-positive/estrogen receptor (ER)-negative, and basal like).[1] The two hormone receptor–negative subtypes are associated with particularly poor outcomes compared to the hormone receptor–positive luminal subtypes.[1-4]

Approximately 10% to 15% of breast carcinomas are known to be “triple–receptor-negative” (ie, not expressing ER or progesterone receptors [PR] and not exhibiting overexpression and/or gene amplification of HER2/neu). Triple-negative breast cancers comprise approximately 85% of all basal-type tumors. As presented in the comprehensive article by Drs. Anders and Carey, a number of studies have focused on understanding the epidemiology, natural history, biology, and treatment strategies for this subtype.[5]

What We Know Today

As clarified by Dr. Anders, it is important to define the terminology used. “Triple–receptor-negative” is a term based on established clinical immunohistochemical and fluorescence in situ hybridization assays for ER, PR, and HER2, whereas “basal-like” is a molecular phenotype defined by using cDNA microarrays.[1,3] When using transcriptional profiling, most triple-negative breast tumors cluster within the basal-like subgroup, but phenotypically there is about a 30% discordance between the two.[6-9] Despite consensus in this regard, most available evidence looks at only one of these groups, and the data are extrapolated to the other.

Epidemiologic findings now illustrate that breast cancer risk factors may vary by molecular subtype. More importantly, such observations are forcing us to reevaluate established breast cancer risk factors and prevention strategies. Important findings discussed in the Anders/Carey paper include the fact that compared to white women, young African-American women have a higher incidence of basal-like disease.[10,11] In addition, patients with basal-like breast tumors are more likely to be associated with an earlier age at menarche, younger age at full-term pregnancy, higher parity, shorter breast-feeding time, higher body mass index, and higher waist-to-hip ratio.[12,13]

Population-based studies have shown lower breast cancer–specific survival rates among those with triple-negative compared to non–triple-negative disease, as well as different patterns of recurrence. Patients with this disease are more likely to relapse during the first 3 years following therapy[14,15] and more commonly develop soft tissue and visceral relapses including CNS metastases.[15] We reviewed a cohort of 679 women with early-stage triple-negative breast cancer in our institution and found that 6.2% of them developed brain metastases, more than half of whom had their first site of metastases located in the brain. As expected, survival following development of brain metastases was poor, with a median of 2.9 months (95% confidence interval [CI] = 2.0–7.6 months; data under review for publication).

Interestingly, despite the poor prognostic features, triple-negative breast cancer is sensitive to standard chemotherapeutic approaches including anthracycline- and taxane-based treatments.[14-17] However, some patients do not respond to standard therapy and have a dismal prognosis.[18]. The discovery of certain molecular characteristics of triple-negative breast cancers is directing us to better understanding the pathophysiology of the disease and to developing more direct therapeutic strategies. It has been observed that most BRCA1-associated breast cancers are triple-negative, and that BRCA1 dysfunctions make cancer cells deficient in double-stranded DNA break repair mechanisms and sensitive to DNA damaging agents such us platinum salts and topoisomerase I inhibitors.[19,20]

Other promising targeted strategies being studied include EGFR-targeted agents, antiangiogenic agents, poly(ADP-ribose) polymerase (PARP) inhibitors, and PI3K pathway inhibitors. Although interesting results are coming from studies of these approaches, they have not yet replaced current standard therapy and should not be used in patients with curable disease outside a clinical trial.

Looking Ahead

We are fortunate that ongoing intense research will allow us to better understand this aggressive disease and hopefully to improve its outcome. Still, there are many questions that need to be solved. For example: How do we incorporate the molecular and epidemiologic data? Are all triple–receptor-negative breast cancers the same at the molecular level? Do African-American patients have the same prognosis as patients of other ethnicities once they are diagnosed with triple-negative disease? Are these breast cancers molecularly different among ethnic groups? If such differences in molecular characteristics and ethnicities exist, should therapeutic approaches be the same?

Investigators from different institutions are trying to solve some of these issues. Using transcriptional profiles to analyze human triple-negative breast cancers, researchers have found at least two molecularly different groups of tumors that appear to be associated with different outcomes (unpublished data).

In an effort to solve some of the ethnicity questions, we looked at 471 patients with triple-negative breast cancer treated with primary systemic chemotherapy to evaluate the effect of race on pathologic complete response (pCR) rates and survival outcomes. A total of 100 patients (21.2%) were classified as African-American. With treatment, 17% (n = 17) of African-American patients and 25.1% (n = 93) of white/other patients achieved a pCR (P = .091). The 3-year recurrence-free survival rates were 68% (95% CI = 56%–76%) and 62% (95% CI = 57%–67%) among African-American and white/other women, respectively, with no significant difference observed between the two groups (P = .302). The 3-year overall survival was similar between the two groups (71%, P = .919). After controlling for patient and tumor characteristics, race was not significantly associated with survival outcomes (data under review).

We have also started to look at genomic discrepancies between ethnicities in triple-negative breast cancer. We have analyzed the transcriptional profiles of 98 triple-negative tumors-19 belonged to African-American patients, 23 to Hispanic patients, and 56 to Caucasian women. We found no evidence of clustering of gene-expression data by ethnicity, or differentially expressed genes in triple-negative tumors among African-Americans compared to Caucasian or Hispanic women after adjustment for multiple comparisons.[21]

These studies are just the beginning of attempts to better understand the epidemiologic and molecular characteristics of this disease. This is important, since in the absence of an understanding of the ethnic diversity of breast cancer, potential markers and targets specific to different populations could be missed.

Finally, ongoing clinical trials are being conducted in efforts to translate these molecular findings in both advanced and early disease to patient care. We are currently studying alternative chemotherapeutic agents such as platinum salts, topoisomerase inhibitors, and epothilones in the neoadjuvant setting. Multiple trials are studying agents targeting angiogenesis, PARP, EGFR, PI3K, and Src pathway inhibition, alone or in combination with chemotherapy in the (neo)adjuvant and metastatic settings.

All these studies will add to the current knowledge of triple–receptor-negative breast cancer. We must continue to identify the tumors that will respond to specific therapies, to develop biologic response modifiers that will improve cancer management, and to decrease the amount of time that it takes to deliver useful drugs to patients.

-Ana M. Gonzalez-Angulo, MD, MSC
-Gabriel N. Hortobagyi, MD

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.

References:

References

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