Understanding and Treating Triple-Negative Breast Cancer: Page 2 of 3
Understanding and Treating Triple-Negative Breast Cancer: Page 2 of 3
The inferior prognosis associated with triple-negative breast cancer was originally recognized in the initial studies examining outcome by intrinsic subtype. These studies uniformly demonstrated a poorer prognosis among patients with breast cancer classified as “basal-like,” particularly compared to those in good-prognosis subclasses (ie, luminal A) via gene expression profiling.[3,4] Interestingly, classic prognostic profiles applied to a set of basal-like breast cancers (ie, 70-gene profile, recurrence score, and activated wound response signature) uniformly gave poor-prognosis signatures despite significant variations in methodology and little overlap in individual genes.
Population-based studies have also demonstrated reduced breast cancer–specific survival among patients with triple-negative disease as compared with luminal phenotypes.[27,28] A recently reported Canadian series evaluating prognosis in over 1,500 women illustrated an increased likelihood of distant recurrence (hazard ratio [HR] = 2.6, P < .0001) and death (HR = 3.2, P < .0001) among women with triple-negative breast cancer compared to non–triple-negative disease. Interestingly, the pattern of recurrence over a 5-year follow-up period was substantially different among groups. Women with triple-negative breast cancer were much more likely to develop a recurrence during the first 3 years following therapy with rapid declines thereafter. Patients with non–triple-negative disease demonstrated more consistent rates of recurrence over the follow-up period.
Patterns of Recurrence
In addition to a distinct pattern of timing of recurrence, we are increasingly recognizing unique patterns of relapse site among triple-negative breast cancer patients. Studies have consistently shown that more aggressive visceral and soft-tissue relapse are more common and bone relapse less common among those diagnosed with triple-negative vs ER-positive disease.[6,36]
Among 344 patients with lymph node–negative breast tumors treated solely with local therapy, the intrinsic gene list was applied to classify molecular subtypes (ie, luminal, basal, HER2-positive, etc), such that site-specific patterns of relapse could be determined. Bone relapse was more likely to occur in luminal subtypes (especially luminal A, P = .056) but less likely in the basal-like phenotypes (P = .0001). Lung metastasis was more frequently observed in the basal-like subtype (P = .01) and less likely among luminal subtypes (P = .019). Finally, of the 14 cases of brain metastasis observed in this series, 8 were basal-like in origin (P = .035) compared to only 2 of luminal origin (P = .0031), indicating a predilection for brain metastasis among patients diagnosed with triple-negative disease.
An estimated 15% of all patients diagnosed with breast cancer will develop brain metastasis. This figure, however, is likely an underestimate, as autopsy studies report a 30% rate of subclinical disease. Despite currently available therapies including corticosteroids, whole-brain radiotherapy, surgical resection, stereotactic radiosurgery, and supportive care, survival following a diagnosis of brain metastasis remains quite poor, with a median survival of only 6 months and 1-year survival approximating 20%.[37,38] The increased incidence of brain metastasis among patients with HER2-positive metastatic breast cancer has been documented for several years, and targeted therapeutics—namely lapatinib (Tykerb)—have shown promise in the treatment of HER2-positive trastuzumab (Herceptin)-refractory, progressive brain metastasis.[39,40]
More recent studies highlight the frequency and aggressiveness of intracranial metastasis in triple-negative breast cancer, although similar systemic strategies are not yet available. In a series of over 3,000 patients with brain metastasis arising from breast cancer treated from 1989 to 2006, multivariate analysis indicated that triple-negative status was the greatest risk factor for the development of cerebral metastasis (odds ratio [OR] = 4.16; P < .001), above that of HER2-positive status (OR = 3.43; P = .005). The median interval between primary diagnosis and cerebral relapse was shorter among patients with triple-negative breast cancer than non–triple-negative (22 vs 51 months, OR = 2.7; P < .0001), with a trend toward worse survival after the diagnosis of brain metastasis (4 vs 8 months; P = NS) .
Another series of 222 patients with brain metastasis treated between 2003 and 2006 also found inferior median survival for patients with triple-negative (3.7 months) vs HER2-positive (9 months) and ER/PR/HER2–positive (15 months) disease (P = .015). Significant efforts are focusing on the prediction of patients at highest risk for subsequent breast cancer–related brain relapse, including both clinical nomograms and gene expression strategies.[42-44] The majority of these efforts, however, have been directed at patients with HER2-positive disease. The above studies provide ample evidence that predictive, preventive, and therapeutic strategies in the setting of triple-negative intracranial relapse remain a challenge.
Although triple-negative breast cancer is associated with a generally poor breast cancer–specific outcome, it is not resistant to chemotherapy (Table 1). In the adjuvant setting, retrospective review of a subset of patients treated on Cancer and Leukemia Group B (CALGB) 9344 suggested that the benefit of a taxane added to an anthracycline was primarily among patients whose disease overexpressed HER2 or were double-negative (ER/HER2), most of which are likely to be basal-like.
Two neoadjuvant studies shed light upon the relationship between chemosensitivity and outcome. Both revealed proportionally higher sensitivity to anthracycline- or anthracycline/taxane–based chemotherapy for basal-like/ER-negative breast cancers compared to luminal/ER-positive subtypes. One study compared clinical response among over 100 patients (32% basal-like [ER-negative, HER2-negative], 10% HER2-positive/ER-negative, 58% luminal [ER-positive]) treated with neoadjuvant AC (doxorubicin [Adriamycin]/cyclophosphamide) chemotherapy and found the highest response rates among those classified as basal-like (85%) and HER2-positive (70%), compared with luminal (47%; P < .0001). Despite initial chemosensitivity, disease-free survival (P = .04) and overall survival (P = .02) remained poorest among those with basal-like and HER2-positive tumors compared to luminal tumors.
A second study evaluated over 1,000 patients (23% triple-negative) treated with a variety of anthracycline/taxane–based neoadjuvant strategies. Consistent with previous results, a higher pathologic complete response was observed among patients with triple-negative disease compared to ER-positive breast tumors (22% vs 11%, HR = 1.53, P = .34). In multivariate analysis, triple-negative status was associated with decreased 3-year progression-free and overall survival compared to non–triple-negative disease (63% vs 76%, HR = 1.86, P < .0001; and 74% vs 89%, HR = 2.53, P < .000; respectively).
In both series, patients with a pathologic complete response had excellent outcomes regardless of subtype. Patients with residual disease following neoadjuvant therapy were at highest risk for recurrence. Thus, the poorer outcome among triple-negative patients was attributed to a higher rate of recurrence among patients with residual disease. These studies of chemotherapy response and patterns of recurrence highlight the value of neoadjuvant studies. They also reveal that while there are patients with triple-negative disease who are well-treated with conventional cytotoxic therapies, this subtype in particular requires more effective upfront therapies capable of eradicating disease.
Traditionally, chemotherapy has been the mainstay of systemic treatment for triple-negative breast cancer, since currently available targeted agents, including endocrine therapy and HER2-directed therapies, are ineffective. As previously mentioned, triple-negative breast cancer is highly responsive to primary anthracycline and anthracycline/taxane chemotherapy; however, a high risk of relapse remains if tumor is not eradicated.[6,46,47] Preclinical and clinical studies indicate that tumors with BRCA1 dysfunction harboring deficient double-stranded DNA break repair mechanisms are sensitive to agents that cause DNA damage, such as platinum agents (cisplatin and carboplatin).[48,49] The association between triple-negative breast cancer and BRCA1 mutation status has led to several (neo)adjuvant and metastatic studies illustrating activity of platinum-based regimens in the treatment of triple-negative breast cancer, although how this activity compares with that of other cytotoxics remains unclear.[50-54]