triple - negative breast cancer ( tnbc ) is characterized by absence of expression of the estrogen ( er ) and progesterone receptors ( pr ) and no human epidermal growth factor receptor 2 ( her2)/neu gene amplification [ 1 , 2 ] . unlike hormone receptor - positive and her2-overexpressing breast cancers , tnbc is unresponsive to endocrine therapy and her2-targeted agents , respectively , thereby limiting available systemic treatment options to conventional cytotoxic chemotherapy [ 1 , 2 ] .
patients with tnbc are more likely to have visceral or brain metastases and short relapse - free survival compared with those with other breast cancer subtypes [ 3 , 4 , 5 , 6 ] . while chemotherapies have been effective for treating early - stage disease , with pathologic complete response ( cr ) rates exceeding those of hormone receptor - positive subtypes , patients with metastatic disease have shorter disease - free survival progressing rapidly through several lines of chemotherapy .
thus , response to chemotherapy has not translated to improvements in progression - free ( pfs ) or overall survival ( os ) in the metastatic setting , and the overall prognosis for tnbc remains poor [ 3 , 7 ] .
the median os of patients with metastatic disease is relatively short , with reports between 9 and 13.3 months [ 3 , 4 , 5 , 6 ] .
an unmet clinical need exists for more effective therapies for tnbc , particularly in the metastatic setting .
taxane - based chemotherapy has demonstrated activity in patients with tnbc [ 1 , 2 ] . in the phase iii eastern cooperative oncology group 2100 trial in which
91% of the patients had her2-negative disease , 51% of the patients were pr negative and 37% were er negative , the addition of bevacizumab to solvent - based paclitaxel demonstrated significantly improved median pfs compared with solvent - based paclitaxel alone ( 11.8 vs. 5.9 months , respectively ) ; however , this did not translate into a significant improvement in median os for the combination arm .
nab - paclitaxel , a novel formulation albumin - bound paclitaxel with a mean particle size of 130 nm , was initially designed with the intent to improve the therapeutic index of solvent - based taxanes [ 9 , 10 ] .
currently , nab - paclitaxel is indicated for the treatment of breast cancer after failure of combination chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy .
a phase ii study examined the combination of nab - paclitaxel , bevacizumab , and gemcitabine as first - line therapy for patients with her2-negative metastatic breast cancer .
in this small cohort of patients with stage iv tnbc , the clinical benefit rate as defined by cr , partial response , and stabilization of disease was 85% .
additionally , in this study , there were no significant differences in pfs or os between triple - negative and hormone receptor - positive patients .
this work reports on a patient with metastatic tnbc enrolled in this phase ii study of nab - paclitaxel , bevacizumab , and gemcitabine who experienced a long - term complete remission lasting just under 2 years and a pfs from diagnosis of nearly 3 years .
in june 2007 , a 52-year - old woman was diagnosed with invasive ductal carcinoma .
the patient initially presented with chest pain , and a subsequent breast examination revealed a mass in the left breast and a palpable sternal mass .
a lumpectomy and axillary lymph node dissection were performed at an outside institution and results revealed a moderately differentiated , infiltrating ductal carcinoma , high nuclear grade , measuring 4 cm in maximal diameter , with metastases to 2 of 24 axillary nodes .
further staging also revealed sternal and mediastinal metastases , and a computed tomography ( ct ) scan revealed bilateral pulmonary nodules ( fig .
tumor samples were negative for er and pr , and positive ( + + ) for her2 by immunohistochemistry .
however , fluorescent in situ hybridization results were negative for her2 gene amplification , and the patient was diagnosed with triple - negative primary metastatic / stage iv breast cancer .
the patient was initially seen at the university of miami sylvester comprehensive cancer center and enrolled in the phase ii study of nab - paclitaxel , bevacizumab , and gemcitabine for her2-negative metastatic breast cancer .
she was treated on study with gemcitabine 1,500 mg / m by 30-min infusion , followed by nab - paclitaxel 150 mg / m by 30-min infusion , then bevacizumab 10 mg / kg by 30-min infusion once every 2 weeks in a 4-week cycle .
the patient experienced pain relief after 5 weeks on the study ( 2 infusions ) .
serial ct scans , performed every 2 months , demonstrated progressive reduction in the size of all target lesions ( fig .
she showed a complete clearance of lesions in all imaging studies , which was confirmed on at least 2 separate occasions approximately 2 months apart according to response evaluation criteria in solid tumors .
one dose reduction , as required by the study protocol , occurred in november 2008 on cycle 12 , due to treatment - related fatigue .
the dose of gemcitabine was reduced to 1,250 mg / m , nab - paclitaxel to 125 mg / m , with no modification of the bevacizumab dose , and treatment was continued once every 2 weeks on a 4 week cycle . throughout her treatment ,
she experienced no major side effects and continued to work uninterrupted except for visits for chemotherapy and evaluation , and her treatment - related fatigue was successfully managed with the dose reduction .
the patient maintained her response and continued to receive treatment for just over 2 years .
after 12 months on study , follow - up was performed every 3 months . in may 2010 , the patient had documented disease progression by ct scan .
metastases were found in the lung , bone , and lymph nodes . as specified in the study protocol , the patient discontinued study treatment due to disease progression .
she received her last dose of nab - paclitaxel , bevacizumab , and gemcitabine on may 28 , 2010 .
three weeks after progressing , the patient received capecitabine at a dose of 2,000 mg / m orally twice a day for 2 weeks in 3-week cycles and showed minor response .
however , therapy was stopped due to unacceptable toxicity , including diarrhea , dehydration , and severe palmar plantar erythrodysesthesia . after 2 months
, she initiated therapy with ixabepilone , with a minor radiographic response . from august 2010
to december 2010 , she received 8 cycles of treatment with ixabepilone ( 30 mg / m ) administered intravenously every 3 weeks . in december 2010 , the patient requested a chemotherapy holiday .
beginning in november 2011 , the patient was treated with eribulin 1.1 mg / m intravenously on days 1 and 8 of a 3-week cycle .
treatment was discontinued in march 2012 due to rapid disease progression with development of central nervous system metastases .
she was transferred to hospice care where she died a month later . throughout the course of her disease ,
she received zoledronic acid at 4 mg intravenously every 4 weeks beginning in november 2007 when she began the phase ii study . in may 2010 ,
she continued to receive denosumab throughout her chemotherapy holiday from december 2010 to november 2011 until discontinuing therapy in march 2012 after being transitioned to hospice care .
patients with metastatic tnbc have a very poor prognosis . in a large analysis of 255 patients diagnosed with tnbc at the md anderson cancer center between 1985 and 2004 ,
the median os of patients with recurrent disease was only 1.0 year ( 95% ci , 0.81.2 years ) for tnbc patients , significantly shorter than the median os of 2.3 years ( 95% ci , 1.92.7 years ) for those with other breast cancer subtypes ( hr , 2.5 ; 95% ci , 1.83.5 ; p < 0.001 ) .
other studies have reported median os times for patients with recurrent or metastatic tnbc between 9 and13.3 months [ 4 , 5 , 6 ] .
while median os has not been specifically assessed in a large patient population initially presenting with metastatic tnbc , it is likely to be similarly poor .
additionally , patients with metastatic tnbc exhibit progressively shorter response durations to successive lines of therapy . in a retrospective analysis of 111 patients with tnbc ( 14%
of whom presented with metastatic disease at diagnosis ) , the median duration of response was only 12 weeks ( range , 073.1 weeks ) to first - line therapy , 9 weeks ( range , 0120.9 weeks ) to second - line chemotherapy , and 4 weeks ( range , 059 weeks ) to third - line chemotherapy .
there is an unmet clinical need for effective therapies that prolong survival for patients with metastatic tnbc . in the absence of curative therapies for metastatic disease ,
the goal of therapy is primarily palliative in nature , leveraging systemic treatment with minimal toxicity to both prolong os and at the same time enhance quality of life by delaying the onset of cancer - related symptoms .
numerous studies have shown that the combination of gemcitabine and a taxane is an effective regimen that is well tolerated with good response rates .
the case described here is of a patient with metastatic tnbc treated with first - line combination chemotherapy consisting of nab - paclitaxel , bevacizumab , and gemcitabine every other week . after only 5 weeks and 2 infusions , the patient experienced significant symptom relief from her pain from bone metastases , including the sternum . following 7 months of treatment , she achieved a complete remission that , with continuous therapy , persisted for nearly 2 years for an overall progression - free period from initial diagnosis of 2 years and 7 months .
following progression , subsequent lines of therapy were able to produce only limited efficacy in disease control .
following her initial progression - free interval of almost 2 years in cr with nab - paclitaxel , bevacizumab , and gemcitabine therapy , subsequent treatment with capecitabine then ixabepilone resulted in short progression - free intervals of only 2 months and 4 months , respectively . while ixabepilone did provide a pfs benefit , it was very modest . from her initial diagnosis in june 2007 ,
the patient survived nearly 5 years , which is greatly improved compared to reported median survival of 913.3 months for stage 4 tnbc [ 3 , 4 , 5 , 6 ] . with the aim to enhance quality of life , systemic treatments with minimal toxicity
while the patient did experience treatment - related fatigue while on nab - paclitaxel , bevacizumab , and gemcitabine combination therapy , this was easily managed with a dose reduction .
in addition to a lengthy complete remission , the patient was able to work uninterrupted throughout her treatment period , a factor that may significantly elevate quality of life for many patients .
this patient initially received treatment as a participant in a phase ii study of nab - paclitaxel , bevacizumab , and gemcitabine as first - line therapy for her2-negative metastatic breast cancer . a large proportion ( 13 of 29 ) of the patients enrolled in this study had triple - negative disease .
overall , this subset of patients demonstrated promising outcomes , with 38% achieving a complete radiographic response and 85% experiencing clinical benefit .
most notably , survival outcomes were almost identical between tnbc patients and those with hormone receptor - positive disease . additionally , severe adverse events appeared to be less frequent in the overall study population relative to results in other published chemotherapy studies in patients with metastatic breast cancer .
this case study demonstrates the potential for triplet chemotherapy with nab - paclitaxel , bevacizumab , and gemcitabine to elicit prolonged responses , potentially prolong os , and improve quality of life for patients with metastatic tnbc .
this combination shows promise for the treatment of tnbc and should be the subject of further investigation in larger randomized trials .
 this is a case study of a 52-year - old female patient diagnosed in june 2007 with primary metastatic invasive ductal carcinoma of the left breast and synchronous metastases in the bone , lymph nodes , and lung . 
 biopsy results of the tumor tissue were negative for the estrogen receptor , progesterone receptor , and human epidermal growth factor receptor 2 ( her2 ) . in november 2007 , she participated in a phase ii study of metastatic her2-negative breast cancer . 
 treatment consisted of systemic chemotherapy with gemcitabine 1,500 mg / m2 , nab - paclitaxel 150 mg / m2 , and bevacizumab 10 mg / kg once every other week . 
 the patient experienced pain relief in her sternum after 5 weeks of chemotherapy , and her analgesic therapy was discontinued . 
 after 7 months , the patient achieved a complete radiographic response , which was maintained for nearly 2 additional years . 
 she continued receiving treatment throughout this period , requiring 1 dose reduction due to fatigue . 
 the patient experienced no other adverse events , including neuropathy , and continued working uninterrupted throughout her treatment . 
 the patient was discontinued from the study in may 2010 after disease progression , almost a full 3 years after diagnosis . 
 the patient showed minimal response to subsequent therapies but had disease stabilization and died from her disease in april 2012 . 
 median overall survival for patients with metastatic triple - negative breast cancer is between 12 and 13.3 months . 
 this patient survived nearly 5 years following diagnosis . 
 this case exemplifies how therapy with nab - paclitaxel , bevacizumab , and gemcitabine may prolong survival , with minimal toxicity , in select patients with triple - negative metastatic breast cancer . 
Introduction
Case Report
Discussion