metaplastic breast cancer ( mpbc ) is an extremely rare breast cancer subtype constituting 0.25% to 1% of all breast cancers .
histopathologically , mpbc is characterized by a heterogeneous phenotype , most commonly with epithelial and mesenchymal components .
mpbc is typically associated with rapid metastasis and poor survival compared to other breast cancer subtypes .
most mpbcs are negative for estrogen receptor ( er ) , progesterone receptor ( pr ) , and her2/neu , and are managed as triple - negative breast cancer .
it has been suggested that the poor prognosis of mpbc could be due to its stem cell - like characteristics .
phosphatidylinositol-4,5-bisphosphate 3-kinase , catalytic subunit  ( pik3ca ) mutations and loss of the phosphatase and tensin gene ( pten ) have been identified in this group , but their prognostic and therapeutic significance is unclear . due to its rarity ,
tumor protein 53 ( tp53 ) mutation and overexpression are present in 20% to 40% of breast cancers , but the incidence and significance of this mutation in mpbc are unknown . herein , we report the clinical course of a 59-year - old african american woman with mpbc presenting with pik3ca and tp53 mutations , who was treated using a molecularly matched therapy .
a 59-year - old african american woman presented with a left - sided breast mass .
the biopsy revealed a triple - negative , poorly differentiated , high - grade invasive ductal carcinoma with necrosis .
clinical staging indicated that the lesion was a t2 stage , n1 or 3 , and m0 with biopsy - proven axillary metastasis and suspicion of internal mammary nodal involvement .
the patient received standard neoadjuvant therapy with weekly paclitaxel ( 12 cycles ) and 5-fluorouracil , adriamycin , and cyclophosphamide ( fac ) ( 2 cycles ) .
subsequently , the patient declined further chemotherapy and underwent a left modified radical mastectomy followed by chest wall radiation .
the surgical pathological report indicated an invasive matrix - producing ( metaplastic ) carcinoma with patchy necrosis and 10% er positivity , pr and her2/neu negative , and stage pt2 n1 with 2 of 25 axillary lymph nodes presenting metastatic carcinoma .
after radiation , the patient started a course of anastrozole , which was later switched to exemestane due to arthralgia . a year after surgery , the patient presented with pulmonary metastases and metastatic lymph nodes in the mediastinum and left internal mammary region ( figure 1 )
the patient 's tumor , including the left breast primary and the left axillary lymph node metastases were profiled separately .
genomic dna polymerase chain reaction - based sequencing , using a next - generation sequencing ( ngs ) platform , was performed to screen for the frequently reported point mutations in a 46-gene panel on the primary and metastatic tissues .
this 46-gene panel was validated using an ngs platform for the detection of frequently reported point mutations in human malignancies in the clinical laboratory improvement amendments - certified molecular diagnostics laboratory at the university of texas md anderson center .
a minimum of 250coverage is required at a given base for the interpretation of a wild - type or variant call .
although the ngs platform is capable of achieving a much higher analytical sensitivity , for clinical purposes , we determined the effective lower limit of detection of this assay ( analytical sensitivity ) for single - nucleotide variations to be in the range of 5% ( one mutant allele in the background of 19 wild - type alleles ) to 10% ( one mutant allele in the background of nine wild - type alleles ) by taking into consideration the depth of coverage at a given base and the ability to confirm low - level mutations using independent conventional platforms . to avoid false negatives , we required that the tumor nuclei represented 20% of the nuclei in the tested sample .
a pik3ca gene mutation was detected in codon 545 , exon 10 ( gag to aag ; p.glu545lys ) and another mutation was found in thetp53 gene in codon 286 , exon 8 ( gaa to aaa ; p.glu286lys ) .
the patient was given a combination therapy of intravenous temsirolimus , 25 mg weekly , plus intravenous bevacizumab , 15 mg / kg , and liposomal doxorubicin , 20 mg / m , once on day 1 every 21 days .
repeat positron emission tomography / computed tomography ( pet / ct ) after two cycles of therapy showed a decrease in the standard uptake value from 12.3 to 3.9 in one intrathoracic lymph node and a decrease from 13.1 to 7.0 in another lesion as well as the complete resolution of the disease in most of the sites on a pet scan , with corresponding anatomic improvement observed on a ct scan ( figures 1,2,3 ) .
pet / ct or ct - chest / abdomen / pelvis was performed every 2 months to evaluate the response .
after seven cycles , the patient requested a month break from chemotherapy related to grade 2 - 3 fatigue .
the patient resumed her therapy with reasonable tolerance and continued with clinical benefit and radiological response .
after 14 cycles of therapy , a plateau of response was reached and the patient developed grade 4 dyspnea .
the rarity , heterogeneity , and clinically aggressive nature of mpbc have made this disease a therapeutic challenge .
since these tumors are largely chemoresistant , the identification of novel targeted therapies is necessary to treat patients with this malignancy .
early identification of targetable molecular aberrations , during the course of the disease , might provide therapeutic benefits , particularly in the absence of other options . in this patient ,
the combination of liposomal doxorubicin , bevacizumab , and temsirolimus was selected based on the strong scientific rationale that the pik3ca mutation is found in approximately 14% to 21% of breast cancer patients referred to early phase clinical trials .
a phase i trial using this combination resulted in a 42% partial response ( pr)/complete response ( cr ) rate in mpbc ( 5 out of 12 patients ) .
moreover , 39% of patients with a pik3ca mutation and/or a pten mutation / loss ( 11 out of 28 patients ) achieved a pr / cr .
previous studies have demonstrated that therapies using mammalian target of rapamycin ( mtor ) inhibitors show a response rate of 35% to 39% in patients presenting with activating mutations of the phosphatidylinositide 3-kinase / akt / mtor ( pi3k / akt / mtor ) pathway when compared to patients who did not have a documented pik3ca mutation ( response rate , 6%-10% ) .
in addition to blocking the mtor pathway , temsirolimus decreases hypoxia - inducible factor  ( hif- ) levels .
it has been shown that resistance to doxorubicin - based therapy is mediated through hif-1. thus , hif-1 inhibition by temsirolimus might increase the sensitivity to doxorubicin .
in addition to this putative synergy , the p53 tumor suppressor gene plays an important role in angiogenesis , apoptosis , and tumor stability .
tp53 mutations are found in approximately 53% of patients referred to early phase clinical trials .
intriguingly , tp53 patients present a longer progression - free survival when treated with bevacizumab in combination with other drugs compared to patients treated without bevacizumab ( 10.97 months vs. 4.37 months ) .
mtor inhibitors can reduce vascular endothelial growth factor ( vegf ) levels , increasing the antiangiogenic effects of bevacizumab .
the fact that mpbc commonly displays vegf and hif- aberrations strengthens the rationale for using this combination .
a clinical trial combining these three agents for mpbc is ongoing and may help us to further define the effect of this combination . in summary , identifying the underlying molecular aberrations in each patient as early as possible is crucial to select the most rational matched treatment regimen .
interestingly , in our case study , the same molecular aberrations were identified in both the primary and metastatic specimens .
in addition to pik3ca mutations , other mutations and gene amplifications have been reported in mpbc .
leibl and moinfar   reported epidermal growth factor receptor amplification in 14 out of 20 patients with mpbc .
the case described in this study is unique in ways other than its specific molecular aberrations .
later analysis of the surgical sample identified a matrix - producing ( metaplastic ) carcinoma with patchy necrosis and 10% er positivity , although er was not detected initially .
another important observation in this patient was the complete resolution of fluorodeoxyglucose ( fdg ) uptake in most lesions after treatment .
using mtor inhibitors can lead to decreased metabolism in cancer cells due to their predominant cytostatic properties .
fdg uptake , which is reflective of metabolic activity , may be a useful biomarker to monitor the response to mtor inhibitor treatments .
additionally , pet / ct might be a better imaging modality than ct alone to evaluate the tumor response in patients treated with mtor inhibitors . in conclusion , mpbc is a heterogeneous breast cancer with no current standard therapy .
patients may benefit from being offered molecular profiling early during the course of the disease followed by a therapy guided accordingly .
liposomal doxorubicin+bevacizumab+temsirolimus is one combination that has a strong underlying scientific rationale , and could be used a valuable therapeutic strategy for patients with mpbc .
 metaplastic breast cancer ( mpbc ) is an extremely rare breast cancer subtype , characterized by a heterogeneous phenotype . 
 mpbc aggressive biology is attributed to its stem cell - like characteristics . 
 since these tumors are largely chemoresistant , novel targeted therapies should be explored . 
 herein , we report the clinical course of a 59-year - old african american woman with mpbc with a pik3ca mutation in codon 545 , exon 10 ( gag to aag ; p.glu545lys ) and a tp53 mutation in codon 286 , exon 8 ( gaa to aaa ; p.glu286lys ) . 
 the same mutations were observed in the primary and secondary sites . 
 the patient was treated with a molecularly matched therapy using a combined antiangiogenic and mammalian target of rapamycin kinase inhibitor strategy that included liposomal doxorubicin , bevacizumab , and temsirolimus . 
 partial remission was achieved . in this report , 
 the scientific rationale underlying the activity of this combination was explored . in conclusion , patients may benefit from being offered molecular profiling early during the course of the disease to receive a therapy guided accordingly . 
INTRODUCTION
CASE REPORT
DISCUSSION