breast cancer is the most common malignancy in women and number one cause of death in women between the ages of 45 and 55 in the united states .
although metastatic disease , considered incurable , is rarely seen at the time of initial diagnosis , approximately 20% of women with operable breast cancer eventually relapse , with about 70% of the relapses as distant metastases [ 25 ] .
approximately 80% of women with metastatic breast cancer have skeletal metastases , which are often the result of bone marrow infiltration of malignant cells with subsequent progression and invasion of the skeletal cortex [ 69 ] .
the most common complications of skeletal metastases are pathologic fractures , spinal cord compression as the result of vertebral compression fracture or extension of the tumor beyond the epidural space , and hypercalcemia [ 79 ] .
furthermore , skeletal metastases sometimes require surgery or radiation therapy to treat pain or an impending fracture .
bone marrow metastases result in the invasion and destruction of the bone tissue matrix by tumor cells .
although bone marrow infiltration by metastases is commonly present among breast cancer patients , total bone marrow infiltration resulting in profound pancytopenia is extremely rare .
a 62 year - old female presented with increased fatigue that was interfering with her activities of daily living .
her breast exam was notable for a fixed , 1 cm left axillary lymph node .
her white blood cell ( wbc ) count was 3.2 k/l , hemoglobin ( hgb ) was 6.8 g / dl , and platelet count was 3 k/l .
multiple imaging studies , including computed tomography ( ct ) of the chest , abdomen and pelvis , as well as a bone scintography were completed as part of the initial diagnostic work up .
the bone scintography scan showed diffuse skeletal metastatic disease involving multiple vertebrae and the pelvis .
a mammogram had also been performed and showed an irregular spiculated nodule in the upper inner left breast .
the patient subsequently underwent a core needle biopsy of an enlarged left axillary lymph node .
the biopsy revealed a metastatic lobular carcinoma strongly positive for both estrogen and progesterone receptors ( er and pr ) and negative for her2 and e - cadherin by immunohistochemical staining . to further evaluate the patient s profound pancytopenia , which required frequent transfusion of packed red blood cells ( prbc ) and platelets , the patient underwent a bone marrow biopsy .
the pathology showed that the metastatic carcinoma had entirely replaced the bone marrow ( figure 1 ) .
the tumor cells were positive by immunohistochemical staining for cytokeratin ae1/ae3 , er and pr , but were negative for her2 , consistent with metastatic breast cancer .
after much discussion of the risks and benefits of therapy in view of profound pancytopenia , the patient initiated systemic therapy with doxorubicin administered as a continuous three day infusion ( 20 mg / m / day ) on a 21 day cycle in the inpatient setting .
a continuous infusion of doxorubicin was selected based on small , prior studies suggesting that acute and chronic toxicities , including bone marrow suppression , may be lessened when doxorubicin is administered as a continuous versus bolus infusion [ 1113 ] .
the doxorubicin dose was reduced by 50% due to increased transaminases that normalized with subsequent cycles of therapy .
the second cycle was given at full dose , but was complicated by febrile neutropenia requiring hospitalization .
after 3 cycles of therapy , continuous doxorubicin was switched to monthly liposomal doxorubicin ( 40 mg / m ) for ease of administration in the outpatient setting since the patient s platelets had sufficiently recovered . as shown in figure 2 ,
approximately four months after commencing treatment , her wbc rose to 5.4 k/l , hgb increased to 11.6 g / dl and platelet count improved to 131 k/l .
approximately thirteen months after beginning the treatment , the patient experienced a near full recovery from her pancytopenia with no evidence of anemia or thrombocytopenia .
her laboratory tests showed wbc of 4.8 k/ , rbc of 4.00 m/l , hgb of 12.8 g / dl and platelet count of 160 k/l at that time , indicating a remarkable response to treatment ( figure 2 ) .
after four cycles of liposomal doxorubicin , the patient was transitioned to endocrine therapy with an aromatase inhibitor , letrozole .
her laboratory profile remained stable 43 months after initiation of continuous doxorubicin . in her last 12 months of life , her disease progressed in the liver , bone , orbit and brain .
she was treated with radiation to the orbital metastasis and brain metastases , but declined further systemic chemotherapy . in her last month of life , her platelets dropped to 15 with normal white blood count and hemoglobin levels .
she ultimately died from complications of metastatic breast cancer 44 months after her initial diagnosis .
. however , bone marrow failure as the herald of this disease is not typically seen .
very limited data exists as to the safest and most efficacious manner to treat patients with profound pancytopenia due to metastatic solid tumor involvement . in this case , the patient s thrombocytopenia was particularly worrisome , requiring daily platelet transfusions .
there was also concern that cytotoxic chemotherapy would exacerbate the patient s thrombocytopenia and increase bleeding risk .
the patient s dramatic response to chemotherapy with full platelet recovery is also highly unusual . for our patient , continuous doxorubicin successfully  unpacked  the bone marrow despite a low baseline platelet level , and without increasing the need for more frequent platelet transfusion or risk of catastrophic bleeding . given the rarity of this presentation , it is currently unknown if the majority of similar patients experience near full recovery of hematopoietic function after initiation of appropriate systemic treatment for metastatic disease .
pancytopenia is not a common presentation in patients with metastatic breast cancer . in several studies ,
pancytopenia was noted as the consequence of adjuvant chemotherapy with alkylating agents and topoisomerase ii inhibitors rather than metastatic disease .
some have suggested that the use of growth factor support such as filgrastim or peg - filgrastim may also contribute to the risk of developing pancytopenia related to myelodysplastic syndrome or acute myeloid leukemia , although that association has not been completely established .
saito et al . reported on a metastatic breast cancer patient with pancytopenia who had evidence of concurrent therapy - related acute myeloid leukemia and bone marrow metastasis . in our case ,
this has rarely been described in the literature and includes both patients with both positive and negative outcomes from therapy . several reports highlight patients who have responded to systemic therapy including low dose capecitabine , endocrine therapy and trastuzumab monotherapy [ 2832 ] .
. reported on a case of a patient with bone marrow metastasis from breast cancer .
the patient developed pancytopenia with disseminated intravascular coagulation ( dic ) and was given weekly paclitaxel therapy with blood transfusion and g - csf injections .
therapy was ineffective and the patient died of gastrointestinal hemorrhage due to complications of pancytopenia that were likely caused by dic and metastatic disease .
our patient experienced similar bone marrow metastasis and pancytopenia , but was able to achieve sustained disease control through doxorubicin chemotherapy followed by aromatase inhibitor therapy , without bleeding complications .
in addition , laboratory tests at the time of diagnosis did not show any evidence of dic in our case .
in addition to continuous doxorubicin , our patient received zoledronic acid as a part of management of osseous metastasis from breast cancer .
many studies have focused on the prevention of breast cancer due to subclinical bone marrow metastasis caused by dormant disseminated tumor cells ( dtcs ) in the bone marrow [ 1921 ] .
although dtcs appear to be associated with a higher risk of distant recurrence , they are not known to cause abnormalities in peripheral blood laboratory tests .
solomayer et al . demonstrated the impact of zoledronic acid on dtcs in primary breast cancer patients .
the authors found that dtc - positive patients treated with zoledronic acid were more likely to become dtc - negative following a 12 month treatment interval and concluded that treatment with zoledronic acid improved the elimination of dtcs .
the role of bisphosphonates in preventing skeletal metastases in patients with high risk early stage breast cancer is controversial [ 20,2327 ] .
the contribution of zoledronic acid in bone marrow recovery in this instance is not known .
breast cancer has a tendency to metastasize to the bone marrow , but does not commonly cause bone marrow failure .
the case presented describes a patient who developed complete bone marrow infiltration by estrogen receptor positive metastatic breast cancer that led to transfusion dependent pancytopenia .
the patient received treatment with continuous doxorubicin and zoledronic acid followed by endocrine therapy , which resulted in complete recovery of normal bone marrow function for 3 years .
drug therapy is a consideration in patients with bone marrow infiltration with good performance status .
 complete bone marrow infiltration with profound pancytopenia is very uncommon in breast cancer . 
 bone marrow metastasis can frequently occur following development of metastatic breast cancer 
 . however , bone marrow failure as the herald of this disease is not typically seen . 
 very limited data exists as to the safest and most efficacious manner to treat patients with profound pancytopenia due to metastatic solid tumor involvement . in this case , the patient s thrombocytopenia was particularly worrisome , requiring daily platelet transfusions . 
 there was also concern that cytotoxic chemotherapy would exacerbate the patient s thrombocytopenia and increase bleeding risk . 
 the patient s dramatic response to chemotherapy with full platelet recovery is also highly unusual . for our patient , continuous doxorubicin successfully  unpacked  the bone marrow despite a low baseline platelet level , and without increasing the need for more frequent platelet transfusion or risk of catastrophic bleeding . given the rarity of this presentation , it is currently unknown if the majority of similar patients experience near full recovery of hematopoietic function after initiation of appropriate systemic treatment for metastatic disease . 