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Evolving Strategies for Management of Early-Stage and Metastatic Triple-Negative Breast Cancer

William J. Gradishar

William J. Gradishar, MD, FASCO, FACP
Betsy Bramsen Professor of Breast Oncology & Professor of Medicine
Director, Maggie Daley Center for Women's Cancer Care
Robert H. Lurie Comprehensive Cancer Center
Northwestern University Feinberg School of Medicine

Introduction to TNBC

Incidence

Triple-negative breast cancer (TNBC) is characterized by lack of estrogen receptor (ER) and progesterone receptor (PR) expression and lack of human epidermal growth factor receptor-2 (HER2) gene amplification or overexpression. The American Cancer Society estimates more than 232,000 new cases of breast cancer and 40,000 deaths from breast cancer in women will occur in 2014.1 TNBC accounts for 15% to 20% of all breast cancer diagnoses2-4 and is a highly aggressive form of breast cancer, leading to disproportionately higher rates of mortality and metastasis.5

Risk factors associated with the development of TNBC include race, age, genetic factors, waist/hip ratio, breastfeeding history, and parity. TNBC typically presents in younger women; diagnoses in women younger than 40 years of age are more common with this subtype.6 TNBC is more common in women who are African-American or of black ethnicity than in other ethnicities.2,6-9

Associations have been identified between typical hormonal changes and increased risk of developing TNBC. Higher parity and younger age at first full-term pregnancy increase the risk of TNBC; however, risk is reduced by breastfeeding, greater number of children breastfed, and increased duration of breastfeeding.10 Obesity may also increase the risk of developing TNBC in both pre- and post-menopausal women, particularly those with BRCA1 or BRCA2 mutations.10,11

The identification of clinicopathological factors associated with TNBC has been hindered by a lack of data on large populations.11 In particular, collection of HER2 status data has been a relatively recent addition to data collection protocols for most cancer registries, first appearing as a routine element in the National Comprehensive Cancer Network (NCCN) Breast Cancer Outcomes Database in 1999 (immunohistochemistry [IHC]) and 2001 (fluorescence in situ hybridization [FISH]). 

BRCA mutations

mutation of BRCA

TNBC has been associated with a higher rate of BRCA mutations compared with other breast cancer subtypes.4,12 Among patients less than 50 years of age who are diagnosed with TNBC and have no family history or known predisposition, 10% to 30% are BRCA1 mutation carriers.13,14 The basal-like breast cancer subtype has also been associated with germline BRCA1 mutations, with 75% of BRCA1-related breast cancers falling into the basal-like sub­type by either IHC or microarray.15,16 Disruptions in DNA repair pathways and BRCA genomic instability appear to be important in both basal-like and BRCA-related breast cancers; thus, there is interest in determining the prevalence of BRCA mutations in TNBC and in predicting outcomes for BRCA-associated and non-associated TNBC. Although BRCA1 mutation prevalence has been well studied among women with known high-risk ancestry, such as those of Eastern European or Ashkenazi Jewish origins, BRCA mutation prevalence among women of other ethnicities and with­out any associated family history is less well understood, particu­larly as these mutations relate to TNBC.17

Studies evaluating BRCA mutation prevalence in TNBC, though different in design and immunohistochemical definitions, con­firm an increased rate of BRCA mutation in TNBC. In a retrospec­tive study of 491 patients with breast cancer referred for BRCA genetic testing, 11.4% had BRCA1 mutations, 6.1% had BRCA2 mutations, and 79.6% were BRCA-negative.12 Of the 93 women with TNBC, 34.4% had BRCA1 mutations, 7.5% had BRCA2 mu­tations, and 58.1% were BRCA-negative. A larger retrospective review of 469 patients with TNBC who underwent BRCA testing showed significant differences in mutation prevalence by race/ ethnicity and age.17 The BRCA1 and BRCA2 prevalences in this TNBC cohort were 23.5% and 7.1%, respectively.

A potential limitation of studies in selected populations, par­ticularly those that focus only on BRCA1, is the likelihood of enrichment for TNBC, which may not accurately reflect a true mutation prevalence. Two recent studies addressed BRCA mu­tation prevalence in unselected cohorts. Gonzalez-Angulo and colleagues evaluated germline and somatic BRCA1/2 mutation incidence in 77 patients by sequencing tumor and normal DNA samples at the BRCA1/2 exons and flanking regions.4 The inci­dence of BRCA mutations in this cohort was 19.5%, with a 15.6% incidence of BRCA1 mutations, including one somatic muta­tion, and a 3.9% incidence of BRCA2 mutations. Patients with BRCA mutations were younger than those without mutations (P = .005), but no association between mutation status and tumor grade, stage, or histology was shown. Interestingly, BRCA muta­tion carriers had significantly better outcomes and lower risk of relapse than non-BRCA mutation carriers, with 5-year over­all survival (OS) of 73.3% versus 52.8% (P = .225) and 5-year recurrence-free survival of 86.2% versus 51.7% (P = .031). Simi­larly, Hartman and colleagues evaluated an unselected cohort of TNBC patients without significant family history of breast cancer (N = 199).18 The authors reported a comparatively low BRCA1 mutation prevalence (6.5%) and a higher than expected prevalence of BRCA2 mutations (4%), in part due to low partici­pation by women of Ashkenazi ethnicity. 

About 20% of TNBC patients will have impairment of DNA re­pair mechanisms resulting from genetic and epigenetic changes that ultimately hinder the BRCA1 pathway, even in the absence of somatic BRCA1 mutations (BRCAness).10 Genomic instability in BRCA1/2 carriers may enhance the activity of DNA damaging drugs, such as platinum compounds, or drugs that prevent DNA repair, such as poly-ADP ribose polymerase (PARP) inhibitors. A comprehensive analysis of breast tumors by The Cancer Genome Atlas Network, integrating data from 6 different high-through­put genomic, proteomic, and epigenomic technology platforms, showed that 20% of basal-like tumors harbor germline and/or somatic BRCA mutations, suggesting that platinum compounds or PARP inhibitors could potentially benefit 1 in 5 patients with basal-like breast cancers.19 This analysis also highlights the pos­sibility of common driving molecular events between basal-like breast tumors and serous ovarian carcinomas, as BRCA1 inactiva­tion, TP53 and RB1 loss, and cMYC amplification were common to both of these cancers. Studies such as this point to a therapeutic approach illuminated by molecular profile, rather than strictly by tissue of origin, which is supported by the activity of taxanes and platinum analogs in both serous ovarian and basal-like breast cancers.10 

Relapse, metastatic disease, prognosis

Outcomes are favorable and comparable to other breast cancer subtypes for patients with TNBC who respond well to neoadju­vant chemotherapy, as determined by achievement of a pathologic complete response (pCR).20,21 Unlike in other subtypes, relapse rates for TNBC are especially high (10%-15%) in the first several years following surgery, with a peak at about 3 years.22-25 Late re­lapses occur less frequently, and most patients with TNBC who eventually present with metastatic disease will have relapsed soon after previous treatment.5,26

Recurrence patterns are also different in TNBC than in hor­mone receptor (HR)-positive tumors. TNBC relapses tend to oc­cur at distant sites, with preferential metastasis to visceral sites including lung, brain, and liver20,23,27 compared with ER-positive breast cancers, which typically metastasize to skin or bone.28 The risk of locoregional relapse in TNBC is a matter of ongoing debate, but data from several studies suggest that patients with TNBC have an increased risk of locoregional relapse following mastectomy.29-32 

Survival after metastatic relapse is shorter for TNBC than for other subtypes, with a median OS of approximately 13 months after diagnosis of metastatic TNBC.11,33 Thus, treatment goals for advanced TNBC center upon prolonging survival, relieving symp­toms, and enhancing quality of life.34-36 

Molecular subtypes of TNBC

TNBC is a highly heterogeneous disease; correspondingly, out­comes are not entirely explained by its clinical characteristics or pathological markers. Most TNBCs are invasive ductal carcino­mas; in approximately 90% of cases, they are poorly differenti­ated, highly proliferative tumors of relatively large size.2,10

In recent decades, a focus on molecular analysis has provided insight into the biology of breast cancers beyond standard clini­cal and pathological features. These approaches should enhance understanding of breast cancer biology and provide insight into the development of targeted therapeutic approaches.

Subtypes of Breast CancerThrough global gene expression analyses, 5 intrinsic subtypes of breast cancer and a normal breast-like group were established (Table 1).37-39 Importantly, the intrinsic subtypes (basal-like, lumi­nal A, luminal B, HER2-enriched, and claudin-low) differ accord­ing to developmental origin, incidence, treatment response, and survival.40 TNBC is most commonly associated with basal-like and claudin-low intrinsic subtypes37; however, the clinical utility of these designations in TNBC remains to be determined.41

More recently, TNBC was further delineated into 7 molecular subtypes characterized according to differential gene expression on microarray.42 These include basal-like 1 and 2 (BL1 and BL2), mesenchymal, mesenchymal stem-like, immunomodulatory, lu­minal androgen receptor (LAR), and unstable (UNS). Most TNBCs are of the basal-like molecular subtypes, characterized by expres­sion of keratins 5, 6, and 17 and overexpression of genes involved in proliferation.38

Correlation of TNBC and Intrinsic SubtypesThe clinical relevance of the 7-subtype molecular classification was recently evaluated in a study of 146 patients with TNBC who underwent neoadjuvant chemotherapy.43 Samples classified by TNBC molecular subtype using gene expression microarray were then correlated with pCR status and compared with intrinsic sub­types. A significant association between TNBC subtype and pCR status was observed (P = .043), and TNBC subtype was shown to be independently predictive of pCR status (P = .022). The highest pCR rates were observed among patients with basal-like 1 TNBCs (52%), with lowest pCR rates for luminal androgen receptor (10%) and basal-like 2 subtypes (0%) (Table 2). These findings suggest that TNBC molecular subtypes are clinically relevant and useful as an independent predictor of pCR status in patients who have undergone standard neoadjuvant chemotherapy. 

Neoadjuvant Treatment for Early-Stage TNBC

Benefits of neoadjuvant treatment

The choice between neoadjuvant and adjuvant chemotherapy is made through evaluation of tumor and lymph node resectability, taking into account the ability to achieve negative margins, and whether or not the tumor can be reduced sufficiently to facilitate breast-conserving surgery instead of mastectomy. Results of the landmark NSABP B-27 study conducted by the National Surgical Adjuvant Breast and Bowel Project showed that survival is not improved by the sequencing of chemotherapy before rather than after surgery44; however, there are several benefits to neoadjuvant chemotherapy.

Rapid chemotherapy responses and high sensitivity to neo­adjuvant chemotherapy are characteristic of TNBC/basal-like tumors, and patients who achieve pCR with neoadjuvant chemo­therapy are expected to have a better prognosis.3,45 Thus, neoadju­vant treatment provides an early opportunity to assess therapeutic response, which can identify patients with a better prognosis and help make later treatment decisions. By decreasing tumor size, neoadjuvant chemotherapy can increase surgical options, allowing for adequate tumor margins and potentially converting patients to candidacy for breast-conserving surgery, which may improve cosmetic outcomes. 

Neoadjuvant treatment is also recognized as a valuable research tool. The neoadjuvant setting is ideal for evaluating the efficacy of new drugs or dosing schedules in the context of a validated surrogate endpoint, for studying the relation­ship between treatment and tumor biomarkers, and for assessment of response to treatment at the level of the individual tumor.46,47

Current guidelines support the recommenda­tion of neoadjuvant chemotherapy for any patient likely to be a candidate for adjuvant chemotherapy.48 

Improved pCR rates among patients with TNBC

Rates of pCR among patients with TNBC receiving neoadjuvant chemotherapy are typically higher than in patients with HR-posi­tive breast cancers receiving the same regimens. Partial complete response rates of 15% to 42% have been reported from various studies in patients with TNBC, with pCR rates as high as 57% in those less than 40 years of age.20,21,45 Despite higher rates of re­sponse in patients with TNBC than in non-TNBC subtypes, the prognoses for these patients are comparable.20,21 Outcomes are significantly worse for patients with TNBC who do not achieve pCR, with increased relapse rates resulting in shorter survival.

For patients with residual disease following neoadjuvant chemotherapy, having TNBC versus non-TNBC correlates with significantly worse survival, especially in the first 3 years after treatment, according to an analysis of prospectively collected data from 1118 patients, 255 of whom had TNBC.20 Among pa­tients with TNBC who fail to achieve pCR, 5-year recurrence rates of 40% to 50% have been reported.20,49 The high rate of re­lapse among patients with residual tumor explains the so-called triple-negative paradox of worse overall outcomes in TNBC de­spite greater sensitivity to chemotherapy.21 The large proportion of TNBC patients who do not achieve pCR represent a pressing therapeutic challenge. 

Prognosis based on pCR or residual disease for patients with TNBC

The association between pCR and favorable prognosis is well es­tablished in breast cancer, in spite of variation between the defi­nitions of pCR used in individual clinical trials.49,50 A stringent definition of pCR, allowing no residual disease in breast or axil­lary lymph nodes, appears to be superior to other pCR definitions and provides the best prognostic information.49

The prognostic value of pCR is known to be limited to certain subtypes of breast cancer, specifically TNBC, luminal B/HER2­negative, and HER2-positive (non-luminal), and is weaker in luminal A or luminal B/HER2-positive subtypes.49 The heteroge­neous response of TNBC to neoadjuvant chemotherapy suggests that molecular subtypes of TNBC may be associated with varia­tion in pCR rates and may be useful for predicting which patients might benefit from standard therapies, as well as for identifying targeted therapies. No correlation between pCR and prognosis in ER-positive tumors has been discovered.

Demonstration of a significant association between pCR and im­provement in OS or recurrence-free survival (RFS) has been an elu­sive goal of neoadjuvant clinical trials. To date, no prospective trials have shown significant association between pCR and improvement in OS or RFS for patients with TNBC. Nevertheless, pCR has been considered a surrogate endpoint in clinical trials for TNBC.49 To evaluate the reliability of pCR as a surrogate for survival, the FDA has initiated a pooled analysis of more than 12,000 patients treated in different clinical trials. This analysis will facilitate accelerated approval of new drugs or combinations that produce significant improvement in pCR in high-risk operable breast cancer, as deter­mined by performance in neoadjuvant trials.51 

Anthracycline and taxane-based regimens

Table 3For patients with early-stage TNBC, anthracycline and taxane­based regimens are standard of care (Table 3). The use of an­thracycline- and taxane-based regimens as neoadjuvant therapy is based largely on data from large adjuvant trials in unselected populations.20,52 Despite documented benefit of these agents in TNBC, there is recognized need for new therapeutic targets. In the phase III GeparTrio trial, in which patients were randomized to receive either docetaxel/doxorubicin/cyclophosphamide or docetaxel/doxorubicin/cyclophosphamide plus vinorelbine and capecitabine prior to surgery,45 a pCR rate of 39% was observed among the subset of patients with TNBC, representing the high­est pCR rate reported to date from a multicenter phase III trial.46

Although a meta-analysis of phase III adjuvant trials found an-thracycline-based regimens to be more effective than cyclophos­phamide, methotrexate, and fluorouracil in prolonging disease-free survival (DFS) in patients with early-stage breast cancer,53 the role of anthracyclines in early-stage TNBC has been chal­lenged in recent trials. Both anthracyclines and taxanes are asso­ciated with serious toxicities; thus, there is interest in predicting which patients will respond to these treatments.

Basal-like breast cancer, S100 expression

In a comparative, randomized neoadjuvant trial, patients with locally advanced breast cancer were treated preoperatively with either single-agent doxorubicin or single-agent docetaxel with the purpose of determining molecular predictors of response to these agents.54 This trial identified low topoisomerase 2a expression, which was preferentially associated with TNBC tumors, and ER-negative status as predictors of sensitivity to doxorubicin. Small tumor size and ER-negative status were predictors of sensitivity to docetaxel. Docetaxel was superior to doxorubicin in basal-like cancers (P = .034). Responses to doxorubicin were poorer among patients with TNBC or basal-like breast cancer than in those with other subtypes, whereas responses to docetaxel were better in pa­tients with TNBC/basal-like cancer than in those with other sub­types. These findings confirm earlier results showing the over­all efficacy between neoadjuvant anthracyclines and taxanes in early-stage breast cancer to be similar,55-57 but they also indicate that taxanes may be even more effective than anthracyclines in patients with TNBC and basal-like subtypes.54 

Anthracycline treatment has been associated with significant cardiotoxicity58; thus, although combinations of anthracycline and taxane remain the standard of care for neoadjuvant therapy of TNBC, there is interest in avoiding unnecessary anthracycline exposure. In a pooled analysis of German neoadjuvant chemo­therapy trials, von Minckwitz and colleagues evaluated the effect of dosing characteristics for standard anthracycline and taxane combination regimens on pCR.59 Data from 3332 patients who had participated in 7 German neoadjuvant trials were analyzed. The trials chosen for inclusion in this pooled analysis had uni­form protocols, and multilevel models were used to correct for heterogeneity in pCR across trials and across treatment arms within the trials. In patients with TNBC, higher pCR rates were observed in patients who received treatment with higher cumula­tive doses of anthracyclines or taxanes (equivalent to >300 mg/ m2 doxorubicin or >400 mg/m2 docetaxel, respectively) com­pared with pCR results in patients who received lower cumula­tive doses of these drugs. Anthracycline dose had a greater effect on HER2-negative tumors (OR 1.61) than HER2-positive tumors (OR 0.83; P for interaction = .14). An increased number of cycles was more strongly associated with pCR in HR-negative tumors (OR 1.04) than in HR-positive tumors (OR 1.35; P for interaction = .046). These results suggest that a more individualized ap­proach to neoadjuvant chemotherapy may be possible, tailoring dose and schedule according to breast cancer phenotype. Patients with TNBC, for example, might benefit from neoadjuvant chemo­therapy that is shorter in duration but higher in cumulative dose.59

Increasingly, combinations of an­thracyclines and taxanes are being supplemented with other agents for investigations in the neoadjuvant set­ting. Platinum drugs, other DNA-dam­aging agents, microtubule inhibitors, tyrosine kinase receptor inhibitors, and PARP inhibitors are among the agents being investigated in this con­text.46 

Platinum-based regimens

There is considerable interest in treat­ment of TNBC with platinum drugs because most TNBCs are basal-like with functional alterations of BRCA1, rendering these tumors sensitive to DNA-damaging agents. Nevertheless, the addition of platinum agents to standard neoadjuvant chemotherapy for early TNBC is controversial, and the optimal sequence and combination are yet to be de­termined.

There have been no ran­domized phase III trials yet to evaluate whether or not treat­ment efficacy is improved with the addition of a plati­num drug to anthracycline-and taxane-containing neoad­juvant therapy.

The randomized phase II CALGB 40603 (Alliance) study evaluated the addition of carboplatin, bevacizumab, or carboplatin plus bevaci­zumab to standard neoadju­vant chemotherapy in patients with stage II-III TNBC (N = 427).60 Addition of carboplatin to weekly paclitaxel and dose-dense doxo­rubicin/cyclophosphamide improved the rate of pCR in the breast (60%) compared with no carboplatin (46%) (OR: 1.76; P = .0018). Addition of bevacizumab to neoadjuvant therapy resulted in pCR for breast of 59% versus 48% without bevacizumab (OR: 1.58; P = .0089). Highest pCR rates were observed in patients receiving both carboplatin and bevacizumab (67%); however, no significant interaction between the drugs was detected (P = .52). In breast and axilla, a 13% absolute increase in pCR was observed among patients who received carboplatin (54%) versus no carboplatin (41%) in addition to neoadjuvant chemotherapy (OR: 1.71; P = .0029). Addition of bevacizumab to neoadjuvant chemotherapy increased pCR for breast/axilla to 52% versus 44% without beva­cizumab, but this increase did not meet predefined criteria for statistical significance (OR: 1.36; P = .0570). The highest pCR rates were achieved with the addition of both carboplatin and bevacizumab to neoadjuvant chemotherapy, indicating an addi­tive effect for these 2 drugs in this setting, though no significant interaction between carboplatin and bevacizumab was detected for achievement of pCR in breast/axilla. Bevacizumab was asso­ciated with increases in serious adverse events, including grade 3 hypertension, infections, febrile neutropenia, thromboembolic and surgical complications, and bleeding. In the carboplatin arm, increases in grade 3 and grade 4 neutropenia and thrombocyto­penia and paclitaxel dose modifications were reported. Carbopla­tin was given in 4 doses at an area under the curve (AUC) of 6 every 3 weeks and was better tolerated than when given continuously at AUC of 2. 

 However, weigh­ing a lack of evidence for OS and RFS benefit in the adjuvant setting reported by the BEATRICE trial, the CALGB 40603 investigators concluded that toxicity out­weighed the pCR benefits of adding bevacizumab to neoadjuvant therapy.60,63 Conversely, results for car­boplatin were consistent with those reported from the GeparSixto study, which reported significant im­provement in the rate of pCR with addition of carboplatin to neo­adjuvant chemotherapy in patients with TNBC.64 In this phase II/III study by the German Breast Group (GBG)/Gynecologic Oncology Working Group-Breast (AGO-B), patients were given a weekly regimen of carboplatin added to paclitaxel and pegylated liposomal doxorubicin for 18 weeks (N = 595). Targeted agents were added to this chemotherapy backbone according to tumor subtype, with TNBC patients receiving bevacizumab. A signifi­cant increase in pCR was observed in the carboplatin arm com­pared with the control arm (46.7% vs 37.2%, respectively; P <.2), and absolute differences of 8% to 10% were seen even when a less stringent definition of pCR was used.

Carboplatin was also evaluated in the multicenter, phase II I-SPY 2 trial, in which investigators evaluated a series of novel agents and combinations along with standard neoadjuvant therapy in women with high-risk stage II/III breast cancer, in­cluding TNBC.65 A pCR rate of 52% was seen with the addition of veliparib and carboplatin to paclitaxel plus anthracycline-based chemotherapy compared with 26% for standard neoadjuvant che­motherapy. I-SPY 2 used a unique adaptive randomization design based on biomarker subtypes to assess multiple novel regimens in small groups of patients in the neoadjuvant setting. This type of trial has the potential to accelerate the process of identifying drugs that are effective for different breast cancer subtypes and to prevent unnecessary chemotherapy. A secondary objective of this trial was to develop a resource for integrating clinical, ge­netic, molecular, and imaging biomarker data that would support real-time biomarker evaluation in future clinical trials. In this analysis, pCR was more highly predictive of RFS when evaluated by subset according to receptor expression.

Overall, recent data provide a strong rationale for further in­vestigation of the platinum salts in TNBC. Table 4 lists platinum regimens used in the neoadjuvant setting. 

Table 4

Non-taxane microtubule inhibitor-based regimens

Neoadjuvant trials of non-taxane microtubule dynamics inhibi­tors, which are more developed in the metastatic setting, have begun to yield data in the neoadjuvant setting. Drugs of this class that are being evaluated for neoadjuvant therapy in TNBC include eribulin mesylate and ixabepilone.

Preliminary results of a phase II neoadjuvant trial in 30 pa­tients with TNBC showed a 45.83% pCR rate for 24 of 30 patients who had completed a regimen of eribulin and carboplatin followed by definitive surgery 3 to 8 weeks later.72 Eight of the 24 patients required dose reduction due to grade 3 or grade 4 neutropenia.

Ixabepilone sensitivity was shown to be higher in ER-negative than in ER-positive patients in a phase II neoadjuvant trial.73 A neoadjuvant trial evaluating the combination of ixabepilone with the anti-EGFR monoclonal antibody cetuximab in patients with TNBC is ongoing (NCT01097642).74 

Treatment of Metastatic TNBC

Treatment of metastatic TNBC is clinically challenging because traditional cell surface receptors are not expressed in this tumor type. In the absence of specifically targeted agents for TNBC, cytotoxic chemotherapy is the foundation of treatment for meta­static disease, using the same drugs as for early-stage disease. The NCCN guidelines recommend that systemic chemotherapy be given for treatment of metastatic TNBC with transitioning to palliative care after 3 sequential lines of chemotherapy or when Eastern Cooperative Oncology Group (ECOG) performance status scores are 3 or above.75 

Recurrence and survival data

Recurrence rates are high for TNBC, and survival after metastatic relapse is shorter than for other breast cancer subtypes. This is partly due to the preferential metastasis of TNBC to visceral sites including lung, brain, and liver,20,23,27 compared with ER-positive breast cancers, which typically metastasize to skin or bone.28 Risk of developing brain metastasis is increased in women with TNBC, and median survival after diagnosis with CNS metastasis is shorter for women with TNBC than for the general metastatic breast cancer population.11,33

Response durations for metastatic TNBC are equally dismal, and rapid relapses are common. Of 111 patients with metastatic TNBC receiving single-agent (67%) or multi-agent (33%) palliative therapy, the median duration of first-line palliative therapy was 12 weeks (range 0-73 weeks), with 78% of patients continuing to second-line therapy. The median duration of second-line therapy was only 9 weeks (range 0-121 weeks), and 49% of patients went on to receive a subsequent therapy, with a median third-line du­ration of 4 weeks (range 0-59 weeks). Whereas the median OS for all metastatic breast cancers ranges from 2 to 3.5 years, the median OS for patients with metastatic TNBC in this retrospective analysis was 13 months (range 1-100 months).76,77 

Locations of metastases

Evidence on the correlation between TNBC and lymph node sta­tus is unclear. Both negative and positive associations, as well as lack of association, have been reported.10,23,78,79 Increasing tumor size has been shown to be unassociated with lymph node involve­ment in BRCA1-related tumors, suggesting a preferential mecha­nism of metastasis in these cancers that is hematogenous, and explaining in part the propensity of TNBC metastasis to the lungs and brain.78 Lin and colleagues found that triple-negative tumors are less likely than HER2-positive or HR-positive/HER2-negative tumors to be node-positive, especially if the tumor is larger than 2 cm.11

When metastatic, TNBC typically spreads to distant visceral sites. An analysis of 1389 women in the National Comprehen­sive Cancer Network (NCCN) Breast Cancer Outcomes Database found that women with TNBC had a greater likelihood of first re­currence in the brain (OR, 3.50), lung (OR, 2.17), or locoregional sites (OR, 1.32) compared with women whose tumors were HR­positive/HER2-negative.11 Fourteen percent of TNBC patients had CNS involvement at initial diagnosis of metastatic disease, and 36% of all patients with documented recurrence of TNBC had CNS involvement at some time in their disease course. 

TNBC responds better to chemotherapy

A number of novel agents with demonstrated activity in other cancers or breast cancer subtypes have been evaluated in TNBC in attempts to identify more targeted approaches. Biological agents, in particular, have been the focus of trials in the metastat­ic setting, typically in combination with cytotoxic chemotherapy. A recent systematic review included trials that compared chemo­therapy to chemotherapy plus a biological agent (bevacizumab, cetuximab, lapatinib, iniparib, sunitinib, or sorafenib).80 Analysis of 10 published phase II or III trials encompassing 5293 patients with metastatic breast cancer (1546 with TNBC) showed no ef­fect on OS with any of the biological agents evaluated. Significant improvement in PFS was observed only with cetuximab and beva­cizumab, suggesting that chemotherapy has a greater impact in this setting than biological agents, at least at the current level of molecular understanding of TNBC. 

Single-agent vs. combination therapy

The question of whether to use single-agent or combina­tion cytotoxic chemotherapy for metastatic breast cancer is consistently addressed in current guidelines.

A Cochrane review of 43 randomized trials comparing single-agent and combina­tion chemotherapy included data from 9742 women with metastatic breast cancer, over half receiving first-line therapy for their metastatic disease. Results showed sta­tistically significant advantages for response, time to progression (TTP), and survival with combination chemotherapy compared with single-agent therapy, but due to greater toxicity with the combination regimens, this analysis did not conclude that combinations were more effective than single-agent thera­py.81 Combination chemotherapy is usually reserved for patients with visceral crisis or other immediate need for response. The NCCN guidelines cite lack of compelling evidence for superior­ity of combination chemotherapy over sequential single-agent chemotherapy.75 The first International Consensus Guidelines for Advanced Breast Cancer strongly recommends sequential single-agent therapy, reserving combination chemotherapy for patients with rapid clinical progression, those in immediate need of dis­ease control and/or relief of symptoms, or those with life-threat­ening visceral metastases.82 The advice to treat metastatic breast cancer with single-agent rather than combination chemotherapy was one of the key recommendations put forth by the American Society of Clinical Oncology in its 2013 Top Five in Oncology list.83 

Preferred NCCN single agents


Table 5There is no standard chemotherapy for metastatic TNBC; thus, the available treatments are those that have been approved for breast cancer in general. The NCCN lists representative drugs as preferred single agents from 4 categories: anthracyclines (doxo­rubicin, pegylated liposomal doxorubicin), taxanes (paclitaxel), antimetabolites (capecitabine, gemcitabine), and other inhibi­tors of microtubule dynamics (eribulin, vinorelbine) (Table 5). No specific algorithm is recommended for sequencing of treatment with these agents; therefore, factors including efficacy, toxicity profiles, patient characteristics and preferences, dosing schedule, and route of administration can be considered in treatment plan­ning. 

Anthracyclines

Three anthracyclines, doxorubicin, pegylated liposomal doxorubi­cin, and epirubicin, are in use for treatment of metastatic breast cancer. Doxorubicin and pegylated liposomal doxorubicin are on the NCCN list of preferred single agents for treatment of meta­static TNBC.75,80

For many patients with metastatic TNBC, anthracyclines and taxanes will already have been given as part of conventional adjuvant and neoadjuvant therapy. Rechallenging with anthra­cycline- and taxane-containing regimens may be possible, but there is scarce data on this approach; therefore, its efficacy has not yet been demonstrated in first- and second-line treatment for metastatic breast cancer.93 Only one prospective phase III trial has addressed anthracycline rechallenge, randomizing patients with advanced breast cancer and prior neoadjuvant or adjuvant anthracycline therapy to receive either docetaxel alone (n = 373) or pegylated liposomal doxorubicin followed by docetaxel (n = 378), with a primary endpoint of TTP.94 Secondary endpoints were objective response rate, OS, cardiac toxicity, and safety. Treatment with sequential pegylated liposomal doxorubicin and docetaxel resulted in a significantly improved median TTP compared with docetaxel alone, increasing from 7 months to 9.8 months (P = .000001). Similarly, overall response rate (ORR) increased from 26% with docetaxel to 35% with the addition of pegylated liposo­mal doxorubicin (P = .0085). Overall survival did not differ signif­icantly between the 2 treatment groups (HR = 1.02; 95% CI: 0.86­1.22). Cardiotoxicity, specifically left ventricular ejection fraction decreases and congestive heart failure, and grade 3 or grade 4 adverse events were similar in both groups, but more hand-foot syndrome and mucocutaneous toxicities were observed with the combination of pegylated liposomal doxorubicin and docetaxel. It is noted that pegylated liposomal doxorubicin is pharmacologi­cally different from non-pegylated doxorubicin; thus, caution is advised in deriving conclusions about the feasibility of anthra­cycline rechallenge, particularly in light of the strong potential for serious cardiac adverse events with cumulative dosing of an­thracyclines.5

There have been no studies evaluating the use of anthracy­cline- and taxane-based regimens in patients treated previously with both anthracyclines and taxanes. 

Taxanes

Taxanes are a highly effective class of drugs in breast cancer. These agents block mitosis and induce cell death by causing premature polymerization of the mitotic spindle.95 Paclitaxel is approved by the FDA for patients experiencing relapse within 6 months after completing adjuvant therapy or progression after receiving combination therapy for metastatic disease.96 Paclitaxel is active in anthracycline-pretreated patients in combination with gemcitabine or docetaxel, regardless of breast cancer pheno­type.97,98

In a phase III trial, paclitaxel demonstrated inferior efficacy against docetaxel, with a median TTP of 3.6 versus 5.7 months and median OS of 12.7 versus 15.4 months, but produced con­siderably fewer grade 3/4 neutropenias (55% vs 93%) and febrile neutropenias (2% vs 15%).99 Results of a retrospective study in taxane-pretreated patients are challenging old beliefs about drug resistance in metastatic cancer. The Taxane Re-Challenge Cohort Study demonstrated that patients with disease recur­rence after taxane-based neoadjuvant or adjuvant therapy can be treated with a subsequent taxane-based therapy for metastat­ic breast cancer without necessarily developing resistance.100 Of 106 patients, 48.6% achieved a partial response and 27% achieved a complete response to first-line rechallenge therapy with a taxane. Outcomes after taxane rechallenge were better in patients with a longer disease-free interval after initial taxane treatment. 

Antimetabolites

Antimetabolites work by disrupting normal metabolic processes within the cell, resulting in inhibitions of growth and cell divi­sion. Two antimetabolites, gemcitabine and capecitabine, are ap­proved by the FDA for use in breast cancer.

A randomized phase II study comparing efficacy and safety of three gemcitabine-based regimens in pretreated patients dem­onstrated an ORR of 48% with gemcitabine and cisplatin, 39% with gemcitabine and vinorelbine, and 35% with gemcitabine and capecitabine. Median survival times were 13, 17.5, and 19.4 months, respectively.101 Gemcitabine has also showed improved activity with cisplatin in TNBC patients versus non-TNBC pa­tients.102

Capecitabine is an orally formulated, tumor-targeted pro-drug that undergoes enzymatic conversion to the antimetabolite 5-fluorouracil (5-FU). Based on phase II activity in patients with anthracycline- and taxane-pretreated metastatic breast cancer, capecitabine was approved by the FDA for single-agent use in this this patient population.103 In the phase II study, capecitabine was given orally at a dose of 1255 mg/m2 twice daily for 14 days of every 21-day cycle to patients who had failed 2 or 3 prior chemo­therapy regimens for metastatic breast cancer including a taxane (n = 74). Nearly all patients enrolled had also received prior an­thracycline therapy (96%). Response rates were 27% for patients previously treated with paclitaxel and 20% for those who received prior docetaxel, for an overall response rate of 26%. Median re­sponse duration was 8.3 months with a median TTP of 3.2 months and median OS of 12.2 months. Grade 3 stomatitis (12.2%), diar­rhea (16.2%), and hand-foot syndrome (21.6%) and grade 4 diar­rhea (2.7%) were reported, and toxicity-related dose reductions were common. Lowering the capecitabine dose to 1000 mg/m2 and adopting a 1-week-on/1-week-off schedule have been shown to improve tolerability without sacrificing efficacy.89,104 

Other microtubule inhibitors

Disruption of microtubules is an effective way to interrupt cell proliferation, and this can be accomplished by different mecha­nisms. Whereas taxanes cause the microtubule to form prema­turely, eribulin prevents microtubule polymerization,105 and vinorelbine causes depolymerization of the microtubule.106 All of these mechanisms ultimately prevent cell growth and division.

Eribulin was approved for use in patients with anthracycline- and taxane-pretreated metastatic breast cancer following results of the phase III EMBRACE trial, which compared physician’s choice to eribulin in 762 patients, including 74% with HER2-neg­ative breast cancer and 19% with TNBC.91 An overall 34% decrease in risk of death was reported with eribulin versus physician’s choice, with risk reduction of 29% for TNBC. Eribulin significant­ly increased median OS to 13 months compared with 11 months with physician’s choice (P =.041).

Phase II and III trials of vinorelbine in metastatic breast cancer demonstrated ORRs of 26% to 41%, median PFS of 4 to 6 months, and median OS of 16 to 17 months.106-108 Most adverse events were hematologic toxicities, with a small percentage of painful periph­eral phlebitis and only rare grade 3/4 peripheral neuropathy.106-108

Other single agents referenced by the NCCN as applicable in metastatic breast cancer include the alkylating agent cyclophos­phamide, the anthracycline epirubicin, taxanes (docetaxel and albumin-bound paclitaxel), the microtubule depolymerization inhibitor ixabepilone, and the platinum drugs cisplatin and car­boplatin.75 Platinum drugs appear to be highly active in BRCA1/2­related cancers, but response rates are not high enough to war­rant preferential use. In the Translational Breast Cancer Research Consortium (TBCRC) 009 study, first-line or second-line treatment of advanced TNBC with either cisplatin or carboplatin resulted in a 30% response rate.109 In the randomized, phase II BALI-1 study, only 10% of patients with advanced TNBC experienced a response with single-agent cisplatin as first-line treatment.99,110 

Study 301 subgroup data

The phase III 301 study included women with metastatic breast cancer who had received more than 3 prior chemotherapy regi­mens, or more than 2 for patients with advanced disease, in­cluding prior anthracycline and taxane treatment (N = 1102). Patients were randomized to either eribulin 1.4 mg/m2 on days 1 and 8 every 21 days or oral capecitabine 1250 mg/m2 twice daily on days 1 to 14 every 21 days.111 Results showed similar efficacy for the 2 agents, with ORRs of 11% and 12% for eribulin and capecitabine, respectively (P = .849). Median OS was 15.9 months with eribulin versus 14.5 months with capecitabine (P =.056). Among HER2-negative patients, median OS was 15.9 months with eribulin and 13.5 months with capecitabine (P = .030). Median PFS was 4.1 months versus 4.2 months for eribulin versus capecitabine, respectively (P =.305).

Subgroup analyses were performed to evaluate any potential benefit with eribulin treatment in subcategories of patients.111 Investigators observed a nonsignificant trend favoring improved OS with eribulin versus capecitabine in patients with advanced disease receiving the drug as either a first-, second-, or third-line regimen. A markedly pronounced survival benefit was observed with eribulin compared with capecitabine in patients with HER2­negative disease (15.9 months vs 13.5 months, respectively; P = .03), ER-negative disease (14.4 months vs 10.5 months, respec­tively; P = .02), and TNBC (14.4 months vs 9.4 months, respec­tively; P = .01). Patients with more than 2 involved organs, those who received anthracycline- and/or taxane-based therapies for metastatic disease, and those with disease progression more than 6 months after their last chemotherapy also experienced a great­er survival benefit with eribulin.

Although results of this study do not demonstrate superiority of eribulin, the subgroup analyses indicate that this could be a promising treatment for metastatic TNBC. 

Factors to Consider When Selecting Treatments

Personalizing goals of chemotherapy in metastatic TNBC

The goals of treatment for metastatic TNBC, as for metastatic breast cancers in general, are relief of symptoms associated with tumor burden; prevention of symptomatic tumor progression; enhancement of quality of life; and prolongation of survival.34-36 In an age in which high-throughput technologies are facilitating identification of targeted therapies by allowing a more biology-driven approach to phase II clinical trial design, it is increasingly possible to individualize treatment selection using molecular and genetic characteristics,112 but optimal treatment selection re­quires consideration of patient and clinical factors as well.

In TNBC, selecting treatments in the metastatic setting is challenging because there is no identified target and no defini­tive algorithm for sequencing therapies. TNBC remains an in­curable disease at present, so the potential benefits of any par­ticular chemotherapy regimen must be balanced with potential harms of therapy.113 Clinical factors such as the patient’s history of cytotoxic treatment, residual toxicities, and resistance to prior treatments, are valuable for narrowing down the list of available agents.34 The decision of whether to use single-agent or combina­tion therapy should be governed by the extent of visceral tumor burden and rapidity of progression.75

Key consideration should be given to patient preferences for convenience, tolerability of side effects, and desires for quality of life. It is important that treatment goals be discussed with each patient and that treatment planning be personalized to the great­est extent possible. 

Tolerance of side effects

Tolerability of side effects can have a considerable impact on quality of life for patients with cancer, and patient preferences regarding tolerability must be taken into account when selecting treatment options. For some patients, hair loss due to treatment is an intolerable side effect; capecitabine is often given as first-line therapy in metastatic breast cancer because it does not cause myelosuppression or hair loss.34 For other patients, hair loss may be an acceptable cost of treatment, but not gastrointestinal side effects. Both cisplatin and carboplatin are cleared renally, but carboplatin produces less nausea and vomiting, less neuropathy, and less nephrotoxicity.114 Fatigue may be of greater concern to the patient who wants or needs to continue working, for exam­ple, whereas a patient anticipating considerable gastrointestinal symptoms may eventually have difficulty completing an oral regi­men. For some patients, disease control is prioritized above any side effects.

Tolerability of a potential regimen should also factor in charac­teristics of the chemotherapy agent, including safety and toxic­ity evidence from trials, and patient characteristics, such as age, performance status, and comorbidities. Single agents have fewer toxicities than combination regimens, which should guide deci­sions for patients with poor performance status. Although no age-related toxicity trends have been observed in trials for metastatic breast cancer, elderly patients are frequently treated with single agents due to the assumption of frailty or tolerability issues, when performance status would be a better indicator of fitness.115-117

Some cytotoxic agents are contraindicated in patients with spe­cific comorbidities. For example, use of anthracyclines is not ad­vised in patients with cardiac comorbidities due to known cardiac toxicities observed with these agents.118,119 

Quality-of-life considerations

In 2012, an interdisciplinary team of more than 100 breast can­cer scientists, health care workers, and clinicians tasked with identifying the most pressing clinical gaps in breast cancer pre­vention and treatment identified “developing interventions and support to improve the survivorship experience” as among the top 10 major clinical needs.120

A cross-sectional survey of women with metastatic breast can­cer reported an overall poor quality of life for this patient popula­tion, with many experiencing pain and uncontrolled symptoms throughout their illness.121,122 Psychological distress, including traumatic stress, depression, anxiety, and loss of self-image, are common among patients with cancer and are associated with de­cline in quality of life.123,124 Psychological distress may be expe­rienced by family members of patients as well. Regular distress screening, when incorporated into cancer care, can provide a foundation for psychological support.125 Health inequalities for older patients, due to underrepresentation in clinical trials and inadvertent ageism in practice, contribute to the poorer outcomes seen in older versus younger patients with breast cancer and can affect quality of life for these patients.22,117,126

Quality of life is increasingly included as an endpoint in breast cancer clinical trials, as in the phase III 301 study, comparing eribulin versus capecitabine in patients with metastatic breast cancer. In this cohort, capecitabine was associated with greater improvements in emotional functioning (P = .03), and eribulin was associated with greater improvements in both cognitive func­tioning (P <.001) and overall quality of life (P = .048).127

Quality of life issues are also recognized as a critical compo­nent of aftercare for the patient with cancer. Programs that en­able patients to self-manage their post-treatment care have been shown to benefit patients’ sense of control and willingness to seek health information and to benefit quality of life.128,129 

Future Treatment Directions in TNBC

The search for molecules and pathways that can be targeted in TNBC remains a chief research focus; however, evidence for TNBC subtype-specific responses to various therapies suggests that TNBC should not be regarded as a single entity.43 Basal-like TNBCs, for example, are thought to be more sensitive to plati­nums and PARP inhibitors, while androgen receptor-expressing TNBCs may have a greater response to PI3 kinase inhibition and androgen blockade.130

DNA-damaging agents under investigation in TNBC, in addition to platinum agents, include the PARP inhibitors olaparib and iniparib. Iniparib showed improvement in PFS and OS when combined with gemcitabine and carboplatin in a phase II trial and in pre-specified analyses of patients with TNBC receiving second- and third-line treatment in a phase III trial.131,132

PI3K pathway mutations are common in TNBC, and PI3K inhi­bition has been shown to create a BRCA-deficient state in TNBC cells, sensitizing them to DNA-damaging agents, such as PARP inhibitors.133 Inhibitors of MEK, HSP-90, programmed death-1 (PD-1), and histone deacetylase (HDAC) are also in clinical in­vestigation for TNBC,130 as is angiogenesis inhibition through VEGF or VEGF receptor blockade.134

Combining targeted agents to ensure complementary inhi­bition of a given pathway is an important treatment approach that could both increase efficacy and reduce the development of resistance. Combinations currently under clinical investigation include PI3K inhibitors with PARP inhibitors or with androgen blockade and platinum agents with mTOR inhibitors, PI3K, or HDAC inhibitors.135 Unraveling the heterogeneity of TNBC will be important in identifying potential future targets and in im­proving rational treatment selection for available therapies. 

Conclusion

TNBC is a complex, heterogeneous subtype of breast cancer with no known molecular target. It is a paradoxically difficult cancer to treat, being both highly sensitive to chemotherapy and quick to relapse. For patients who respond to neoadjuvant che­motherapy, as indicated by achievement of pCR, the prognosis is favorable and comparable to that seen with other types of breast cancer. However, most patients have residual disease after neo­adjuvant treatment, and for these patients the prognosis is poor.

Neoadjuvant and adjuvant chemotherapy are thought to pro­duce equivalent outcomes in breast cancer, but neoadjuvant treatment has the advantage of giving an early glimpse at thera­peutic response. Additionally, neoadjuvant chemotherapy may decrease tumor size enough to allow a better outcome through breast-sparing surgery. The neoadjuvant setting provides an op­timal environment for trying potential new therapies, and inno­vative clinical trial designs are beginning to exploit this feature.

Even though molecular studies are providing useful informa­tion that increases understanding of tumor biology and assists in the clinical decision process, identifying specific targets for treatment of TNBC remains an elusive goal. Cytotoxic chemo­therapy is still the standard of treatment for TNBC, with anthra­cycline- and taxane-based regimens forming the basis for treat­ment in the neoadjuvant and metastatic settings.

Sequential, single-agent chemotherapy is the standard of care for metastatic disease. This approach has been determined to be as effective as combination chemotherapy while reducing toxici­ties and the likelihood of needing a dose reduction. The NCCN lists preferred single agents, but optimal sequencing of these agents is not specified. In patients who fail first-line treatment for metastatic breast cancer, evidence suggests a decreasing benefit of treatment beyond the second- and third-line settings.

Factors to be considered when selecting treatments include clinical, pathologic, and molecular features and breast cancer subtype. In light of the lack of targets for TNBC, consideration of clinical trials in the neoadjuvant, adjuvant, and early metastatic settings should be strongly encouraged. Patients should partici­pate in treatment planning, with individualization of treatment according to patient preferences, comorbidities, treatment his­tory, and quality of life concerns. 

References provided after next section, "Q&A With a Community Oncologist."

Q & A With a Community Oncologist:

YardleyDenise A. Yardley, MD
Sarah Cannon Research Institute
Tennessee Oncology, PLLC

Q:  On what basis do you choose from the available neoadjuvant treatments for a patient with triple-negative breast cancer?

A: Triple-negative breast cancer (TNBC), while it accounts for only 15% to 20% of breast cancers in the US, does account for a disproportionate share of the morbidity and mortality due to its aggressive behavior, higher incidence in younger women, and lack of effective targeted therapies. Based on the fact that these are very high-grade lesions, and they express a basal-like pheno­type, when you evaluate them by gene microarray expressions, these are tumors for which I typically use the most active agents in breast cancer. This would typically involve a combination che­motherapy program that usually incorporates administration of anthracycline and taxanes either concurrently or sequentially to offer the chance of having a higher pCR rate at the time of surgery. There are a variety of schedules as well; some are dose dense; some involve a weekly schedule. But I think incorporating the 2 groups of active agents with the anthracyclines and taxanes has been shown to yield the best responses at the time of surgery. 

Q:  How do you make that decision about which schedule to use for patients with TNBC?

A: I would say considerations include the physiologic age of the patient; their other comorbid conditions; and whether a dose-dense schedule, requiring a return visit to receive growth-factor support the next day, is feasible. A patient receiving a concurrent schedule would need a lot of stamina to be able to undergo the chemotherapy. 

Q:  What is the role of platinum agents and non-taxane microtubule inhibitors in TNBC?

A: I think we have a lot of data that support the role of the plati­num agents as a single agent in some patients with aggressive triple-negative disease or BRCA-like disease. The use of plati­num chemotherapy is really based on similarities of the BRCA-associated breast cancers and the sporadic TNBCs, in addition to the single-agent activity of the platinums. There is great interest now in adding these platinum analogs to our neoadjuvant che­motherapies. Most recently, 2 trials were presented: the CALGB 40603 by Sikov and colleagues,1 and then our European col­leagues with GeparSixto evaluated a weekly carboplatin sched­ule.2 Both of these studies suggested that the addition of neoad­juvant carboplatin to treatment significantly increased pCR rate in this setting.

There is still no defined role for a biologic or targeted agent in the preoperative setting despite knowledge of a plethora of these regulated pathways, but it does seem that the platinums have emerged as adding some benefit. We know these platinum salts bind directly to the DNA, and they result in this formation of DNA platinum adducts that crosslink and impair cell division.

The question remains as to whether platinums have an impact as a single agent; they resulted in an excellent pathologic re­sponse when added to a chemotherapy program with a taxane at the time of surgery, but we still do not know whether they impact overall disease-free survival and overall survival (OS)—these data are not yet mature. But use of platinums does seem to increase the eradication of disease at the time of surgery. However, toxicity is also increased, and so some patients certainly have more dose reductions and even some of them have missed a treatment due to the increased toxicity by adding another chemotherapeutic agent.

Several trials are planned to evaluate the platinums further. One interesting study was the I-SPY2 study,3 presented at the San Antonio Breast Cancer Symposium in December. This study evaluated the addition of veliparib/carboplatin to weekly pacli­taxel followed by 4 cycles of doxorubicin/cyclophosphamide- (AC­) based standard neoadjuvant therapy for high-risk breast cancer. The estimated pCR rate was 52% with the veliparib/carboplatin addition to paclitaxel followed by AC versus 26% with chemother­apy alone, with a 95% probability that this regimen is superior to the control. A large 3-armed trial is now under way that hopefully will confirm these initial results. 

Q:  How do the results from the 301 study affect treatment selection in metastatic TNBC?

A: In the EMBRACE trial,4 eribulin was shown to demonstrate an advantage in terms of disease control and overall survival in a very heavily pretreated group of advanced breast cancer pa­tients. Now, that trial certainly was compared with a standard of care where most patients received vinorelbine, gemcitabine, or capecitabine, and it was superior in that particular trial with an overall survival advantage of 10½ to 13 months.

Study 301,5 examined whether eribulin would be effective for less heavily pretreated patients and included a standardized con­trol arm, capecitabine. Half of the approximately 1000 patients had received only 1 prior regimen for advanced disease. The co­primary endpoints were overall survival and progression-free survival (PFS). While, the primary endpoint of this trial was not met, there clearly was a trend for an OS advantage. We could cer­tainly say from that trial that eribulin appears to be just as active and effective as another efficacious drug, ie, capecitabine. So it is clearly equivalent, in efficacy, to one of our best drugs. I think the question becomes, with this trend in OS, whether we can identify the population in the metastatic setting that may derive more or preferential benefit, and subgroup analysis suggests that there was an advantage in the TNBC group with eribulin therapy.

I think the other interesting aspect that has come from that trial is regarding the global health and overall quality of life—this has certainly improved over time but is more pronounced in the eribulin-treated patients—even cognitive function improved sig­nificantly in the patients treated with eribulin. 

Q:  How do you go about arriving at and defining a personalized treatment approach for patients?

A: My personalized approach for patients with triple-negative advanced disease, is first to do a rebiopsy. Even though I know they have a history of TNBC, I reevaluate for any discordance between previously known HER2-negative expression; in the metastatic setting there is a 20% to 25% discordance rate with HER2 expression based on primary tumor status, and there may even be changes in estrogen and progesterone receptor expres­sion. I do look for—depending on the patient—androgen receptor expression. Those patients tend to have a history and course that is similar to that of patients with hormone-positive disease, and several trials are evaluating treatments that affect the androgen receptors, for example, enzalutamide and bicalutamide.

I also conduct molecular profiling of these tumors to look for molecular aberrations for which there may be drugs in clinical development. The signals evolving in the triple-negative popula­tion may lend me then to focus on a clinical trial. There are some interesting data with immune therapies and the PD-1/PD-L1 drugs that suggest patients with TNBC may benefit. So I try to start building an armamentarium of possible clinical trial choices for the patient that they may be eligible for at that point or down the road, as well as going through my standard chemotherapy treatment options. I talk to the patient about setting out the plan to try to determine all possible avenues to target this tumor, both investigational and conventional.

With regard to selecting chemotherapy, there is a large first-line international trial right now, the tnAcity trial,6 which is com­paring nab-paclitaxel in combination with either gemcitabine or carboplatin with the combination of gemcitabine and carboplatin as first-line therapy in metastatic TNBC. In patients with very symptomatic aggressive relapses or with lots of visceral disease or de novo stage IV disease presentations, my approach is to con­sider these patients as candidates for doublet chemotherapy. By contrast, for a patient who has a less aggressive relapse, I may consider using sequential single agents.

It is encouraging that we have, in the treatment of all breast cancer patients, become closer to being able to deliver a personal­ized treatment approach based on breast cancer phenotypes and incorporating molecular features of the tumor partnered with the patient considerations of treatment goals, treatment schedule, mode of treatment administration, quality of life, and toxicities. 

References

Primary Article - William J. Gradishar, MD, FASCO, FACP

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Q & A With a Community Oncologist - Denise A. Yardley, MD

1. Sikov WM, Berry DA, Perou CM, et al. Impact of the addition of carboplatin (Cb) and/or bevacizumab (B) to neoadjuvant weekly paclitaxel (P) followed by dose-dense AC on pathologic complete response (pCR) rates in triple-negative breast cancer (TNBC): CALGB 40603 (Alliance). Paper presented at: 36th Annual San Antonio Breast Cancer Symposium; December 10-14, 2013; Abstract S5-01.

2. von Minckwitz G, Schneeweiss A, Loibl S, et al. Neoadjuvant carboplatin in pa­tients with triple-negative and HER2-positive early breast cancer (GeparSixto; GBG 66): a randomised phase 2 trial. Lancet Oncol. 2014 Apr 30. pii: S1470­2045(14)70160-3. doi: 10.1016/S1470-2045(14)70160-70163.

3. Rugo HS, Olopade O, DeMichele A, et al. Veliparib/carboplatin plus standard neo­adjuvant therapy for high-risk breast cancer: First efficacy results from the I-SPY 2 TRIAL. Paper presented at: 36th Annual San Antonio Breast Cancer Symposium; December 10-14, 2013; San Antonio, TX. Abstract S5-02.

4. Cortes J, O’Shaughnessy J, Loesch D, et al. Eribulin monotherapy versus treatment of physician’s choice in patients with metastatic breast cancer (EMBRACE): a phase 3 open-label randomised study. Lancet. 2011 Mar 12;377(9769):914-23. doi: 10.1016/S0140-6736(11)60070-6.

5. Kaufman PA, Awada A, Twelves C, et al. A phase III, open-label, randomized, mul­ticenter study of eribulin mesylate versus capecitabine in patients with locally advanced or metastatic breast cancer previously treated with anthracyclines and taxanes. 2012 San Antonio Breast Cancer Symposium. Abstract S6-6. Presented December 7, 2012.

6. ClinicalTrials.gov. Evaluate risk/benefit of nab paclitaxel in combination with gemcitabine and carboplatin compared to gemcitabine and carboplatin in triple negative metastatic breast cancer (tnAcity). http://clinicaltrials.gov/ct2/show/ record/NCT01881230. Accessed May 12, 2014. 

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