REVIEW

Fatal hepatitis B reactivation due to everolimus in metastaticbreast cancer: case report and review of literature

Eleonora Teplinsky • Derrick Cheung • Ilan Weisberg • Ramon E. A. Jacobs •

Martin Wolff • James Park • Kent Friedman • Franco Muggia • Komal Jhaveri

Received: 21 August 2013 / Accepted: 21 August 2013 / Published online: 4 September 2013

� Springer Science+Business Media New York 2013

Abstract Hepatitis B reactivation can occur with cyto-

toxic chemotherapy in patients with hepatitis B and cancer.

Reactivation can occur in a patient with chronic hepatitis,

an inactive carrier, or one with resolved hepatitis. Clinical

presentation may range from subclinical elevation of liver

enzymes to fatal fulminant hepatic failure. Mammalian

target of rapamycin inhibitors, which include everolimus,

are a new generation of targeted agents that are currently

approved for many cancers (since March 2009) including

advanced hormone receptor positive, human epidermal

growth factor receptor 2-negative breast cancer, in con-

junction with exemestane (as of July 2012). We are

therefore still learning the various adverse events that occur

with this new class of agents. Here, we present an unfor-

tunate case of fatal hepatitis B reactivation in a woman

with metastatic breast cancer treated with everolimus and

exemestane. We have detailed the controversies around

hepatitis B screening prior to immunosuppressive therapy.

Clinicians and patients should be aware of this rare but

fatal complication prior to everolimus use, and a detailed

history, screening for hepatitis B and prophylactic antiviral

treatment should be considered.

Keywords Hepatitis B virus � Everolimus � Breast

cancer

A 56-year-old Honduran woman who immigrated to the

United States 26 years ago was diagnosed with stage IIIA

(pT1cN2M0) invasive ductal carcinoma of the right breast:

5/11 lymph nodes involved, estrogen receptor positive

(ER?) and human epidermal growth factor receptor 2

negative (HER2/neu negative) in 2002. After lumpectomy

and axillary node dissection in February 2003, she received

adjuvant chemotherapy with Adriamycin and Cytoxan

(AC) followed by paclitaxel (T). She then received adju-

vant radiation and five years of adjuvant anastrazole. Her

past medical history was significant for hypertension, type

II diabetes mellitus (diet controlled), depression, gastro-

esophageal reflux disease, and osteoarthritis. Her home

medications included esomeprazole, sucralfate, and que-

tiapine. She denied any allergies or toxic habits. Family

history was noncontributory. Gynecologic history was

pertinent for menarche at age 18 and menopause since

2003. She is gravida 4, para 3, and denied taking any oral

contraceptives or hormone replacement therapy.

In July 2011, when she developed cough and bone pain,

she was first seen by our service. Positron emission

tomography/computed tomography (PET/CT) done at an

outside hospital showed hilar and mediastinal lymphade-

nopathy, multiple lytic bone lesions, lung nodules, intra-

muscular metastases, and a faintly fluorodeoxyglucose

(FDG) avid pancreatic lesion. Biopsy of an iliac lesion

confirmed metastatic breast carcinoma (ER? [90 %],

progesterone receptor (PR) negative [0 %], and HER2/neu

E. Teplinsky � F. Muggia � K. Jhaveri (&)

New York University Cancer Institute, New York, NY 10016,

USA

e-mail: Komal.Jhaveri@nyumc.org

D. Cheung � I. Weisberg � M. Wolff � J. Park

Division of Gastroenterology, Department of Medicine,

New York University School of Medicine, New York, NY, USA

R. E. A. Jacobs

Department of Medicine, New York University Langone

Medical Center, New York, NY, USA

K. Friedman

Division of Radiology, New York University Langone Medical

Center, New York, NY, USA

123

Breast Cancer Res Treat (2013) 141:167–172

DOI 10.1007/s10549-013-2681-0

negative). She was started on fulvestrant and denosumab.

In August 2011, magnetic resonance imaging (MRI) of the

brain was performed because of headache, which revealed

diffuse osseous metastatic deposits and a 5 mm punctuate

lesion in the left cerebellum for which she underwent ste-

reotactic radiation surgery. She did not have any compli-

cations from this procedure and did not require prolonged

steroids. She had stable disease until February 2013 when

tumor markers (Ca 27.29 and carcinoembryonic antigen

[CEA]) began to rise, and repeat PET/CT showed pro-

gression in the intramuscular metastases, lung nodules and

pancreatic lesion, and new right hilar and intraabdominal

lymphadenopathy. Repeat biopsy of the intramuscular

metastases was performed to confirm her biomarker profile,

which was unchanged. Genetic testing done at this time

was negative for BRCA 1/2 mutations.

Given the extent of disease progression, she was initi-

ated on everolimus, a mammalian target of rapamycin

(mTOR) inhibitor, at 10 mg orally daily in combination

with exemestane at 25 mg orally daily on February 19,

2013. She developed grade 2 diarrhea, mouth sores, fati-

gue, grade 1 elevation of her liver enzymes, and hyper-

glycemia for which everolimus was held on March 6, 2013

and then restarted again at 5 mg by mouth daily on March

25, 2013, with resolution of her symptoms. Her tumor

markers started declining and a follow-up PET/CT on June

3, 2013 showed an excellent response in all of the disease

sites (Fig. 1). Incidentally noted was a new focus of met-

abolically active confluent lung consolidation concerning

pneumonia. The patient was asymptomatic. Everolimus

was held, and 3 days later, the patient developed a cough

with blood-streaked sputum and decreasing exercise tol-

erance requiring admission to the hospital for further work-

up. Her vital signs and physical exam were normal. Viral

cultures were positive for rhinovirus and echovirus, and the

patient was diagnosed with a respiratory viral infection.

She was evaluated by a pulmonologist and ruled out for a

bacterial pneumonia or noninfectious pneumonitis. She

symptomatically improved and was discharged home

within 48 hours without any new medications/antibiotics.

Everolimus was not restarted prior to discharge.

Twelve days after discharge, she presented with new

onset epigastric pain, nausea, decreased appetite, pale

stools, and dark urine. Physical exam was significant for

jaundice. Laboratory data were pertinent for grade 4

transaminitis: Aspartate transaminase (AST) 3265 U/L

(reference range 15–56 U/L), Alanine transaminase (ALT)

1758 U/L (reference range 11–50 U/L), alkaline phospha-

tase 154 U/L (reference range 39–117 U/L), total bilirubin

8 mg/dL (reference range 0–1 mg/dL), and direct bilirubin

4.4 mg/dL (reference range 0–0.3 mg/dL). Hepatitis B

virus (HBV) serologies were checked and revealed acute

HBV infection. Hepatitis B surface antigen (HBsAg) and

Hepatitis B core total antibody (HBcAb) were positive,

while Hepatitis B surface antibody (HBsAb) was negative.

Hepatitis B core IgM antibody was negative. HBV DNA

PCR was positive at 8 log IU, and ultra quantitative DNA

PCR was 106,000,000 IU/mL. Upon further questioning,

the patient’s family revealed that the patient might have

had an exposure to HBV from a blood transfusion in the

postpartum setting in 1989. Later, they were informed that

she had ‘‘cleared the infection,’’ and her liver enzymes

were normal. The patient was immediately started on ten-

ofovir on hospital day 2 under the guidance of the hepato-

biliary service. During her hospitalization, she was clini-

cally stable and had an initial improvement in her AST and

ALT with a reduction in HBV DNA PCR to 1,400,000 IU/

mL. However, she later developed rising lactate and INR,

hypophosphatemia, and hypoglycemia, concerning ful-

minant hepatic failure. AST declined to 877 U/L, ALT

declined to 509 U/L and INR increased to 3.4, further

suggestive of fulminant hepatic failure. Her tenofovir was

switched to lamivudine due to the rising lactate and acute

renal failure. She ultimately developed encephalopathy,

hepatorenal syndrome, and multiorgan failure and suc-

cumbed to death 2 weeks after her admission.

Discussion

Treatment with exemestane and everolimus has been

shown to have a statistically significant 6.5 month

improvement in progression-free survival when compared

to exemestane plus placebo in patients with ER?HER2-

negative metastatic breast cancer [1]. Our patient had a

significant improvement in disease burden, however,

developed fatal HBV reactivation, as evidenced by marked

elevated transaminases and hyperbilirubinemia, and posi-

tive HBV serologies and titers. The positive HBcAb and

negative IgM HBcAb are consistent with past exposure to

HBV. The remote history of a blood transfusion in 1989

perhaps explains her prior HBV exposure; however, no

definitive records were available to confirm this history.

She was not on any new medications, and all other etiol-

ogies for acute hepatic failure were excluded. Since the

initiation of everolimus, she had grade 1 transaminitis

(AST ranging from 60 to 70 U/L and ALT ranging from 80

to 90 U/L), which is a common adverse effect associated

with this drug. In the BOLERO-2 (Everolimus in combi-

nation with exemestane in the treatment of postmenopausal

women with estrogen receptor positive locally advanced or

metastatic breast cancer who are refractory to letrozole or

anastrozole) trial, which led to the food and drug admin-

istration (FDA) approval for everolimus in this setting, 13

and 11 % of patients had increased AST and ALT levels,

respectively; however, there was no occurrence of

168 Breast Cancer Res Treat (2013) 141:167–172

123

fulminant hepatic failure or deaths attributed to hepatic

failure [1].

Everolimus is also approved for progressive neuroendo-

crine tumors of pancreatic origin (PNET), advanced renal

cell carcinoma after failure of treatment with sunitinib or

sorafenib, subependymal giant cell astrocytoma (SEGA),

and SEGA associated with tuberous sclerosis [2]. HBV

reactivation has been described in the product information

for everolimus, and this information was revised recently to

communicate that HBV reactivation can be fatal [3]. There

have been two case reports in patients with renal cell carci-

noma, one of which also had a fatal outcome [4, 5]. Fur-

thermore, in the RADIANT-3 trial of everolimus versus

placebo in pancreatic neuroendocrine tumors, one patient out

of the 204 treated developed fatal HBV reactivation [6].

There were no reports of HBV reactivation in the other

pivotal everolimus trials [1, 7–9]. After an extensive litera-

ture search, we report the first case of fatal HBV reactivation

in a patient with metastatic breast cancer.

Approximately two billion people worldwide have been

infected with HBV, and chronic carriers have a 15–40 %

lifetime risk of developing complications of liver disease

[10]. The prevalence of HBV carriers around the world

ranges from 0.1 to 2 % in low prevalence regions, which

include the United States, Canada, and Western Europe. In

high prevalence regions, such as southeast Asia, China, and

sub-Saharan Africa, the prevalence ranges from 10 to 20 %

[11]. Our patient is from Honduras, which has a HBV

prevalence ranging from 2 to 8 % [12]. A systematic review

recently estimated that the total prevalence of chronic HBV

in the United States may be as high as 2.2 million, with

approximately two-thirds of individuals being foreign born

[13]. According to a study by Yeo et al. [14] in Hong Kong,

the carrier rate of HBV in cancer patients in several

developing countries can be as high as 12 %, and such

patients are at risk for HBV reactivation during or after

chemotherapy treatment. HBV reactivation is defined as a

recurrence or abrupt rise in HBV DNA replication (usually

[1 log10 above baseline) in patients with inactive or evi-

dence of resolved HBV infection [15]. The proposed

mechanism of reactivation is the formation of a covalently

closed circular DNA in the nuclei of the infected hepatocytes

within 24 hours of HBV infection, which leads to HBV

persistence [16]. Three phases of HBV reactivation have

been reported: (1) increase in viral replication, (2) appear-

ance of disease activity, and (3) recovery. Not all the patients

experience all the three phases, and some develop clinically

apparent hepatitis which can result in acute liver failure and

death. Reactivation typically occurs in HBsAg carriers with

inactive or minimally active disease and clinical significance

is associated with pre-chemotherapy liver function [17, 18].

Loss of HBsAg and development of HBsAb and HBcAb

after acute HBV infection have been thought to represent

clearance of HBV [19]. Studies also indicate that a low level

of virus replication still persists in the liver and peripheral

blood mononuclear cells. This can be reactivated in an

immunocompromised state and this rare phenomenon,

known as reverse seroconversion, has been implicated in

HBV reactivation. The suggested mechanism is that of

immune reconstitution: there is an increase in viral replica-

tion in the liver during the period of immunosuppression

followed by an immune-mediated destruction of infected

hepatocytes after discontinuation of immune therapy [17,

20]. For those who do develop HBV reactivation, the fatality

rate ranges from 5 to 40 % [10, 21]. Unfortunately, we nei-

ther had a clear history of hepatitis B infection in the past nor

were we able to obtain any prior hepatitis serologies to

suggest if she was a chronic carrier or had resolved hepatitis.

Fig. 1 PET–CT MIP images pre- (a) and post- (b) treatments with everolimus and exemestane

Breast Cancer Res Treat (2013) 141:167–172 169

123

HBV reactivation can also occur spontaneously, but

more commonly is triggered by immunosuppressive treat-

ment for cancer, autoimmune diseases, or organ trans-

plantation [10, 17, 22]. The risk of developing HBV

reactivation is higher in breast cancer patients who receive

chemotherapy (28–56 %), compared to other solid tumors

(14–21 %) [23]. This could be related to the amount of

immune suppression caused by anthracyclines and steroids,

which are commonly used in breast cancer [23]. Other

cytotoxic agents that have also been associated with HBV

reactivation are listed in Table 1 [4, 19, 24]. Notably,

although our patient did receive anthracycline-based che-

motherapy and steroids, she had no complications and her

liver function tests (LFTs) were normal prior to initiation

of everolimus.

While everolimus has anticancer activity, it also has

immunosuppressive effects. This is because mTOR is

involved in blocking interleukin (IL)-2 signaling, which

plays an integral role in suppressing Th1-cell function and

inducing T cell growth, thereby controlling cellular

immunity [5]. Moreover, Teng et al. [25] reported that

mTOR can have a negative feedback regulation of the

HBsAg synthesis and therefore mTOR inhibition could

induce HBV replication.

Despite the known potential for HBV reactivation in

patients receiving cytotoxic therapy, the practice guidelines

for HBV screening differ among organizations. In 2008,

the United States Center for Disease Control (CDC)

recommended that all patients needing immunosuppressive

therapy should be tested for all markers of HBV infection

including HBsAg, HBcAb, and HbsAb. All patients who

are HBsAg positive should be treated and patients who are

HBcAb-positive should be monitored closely for signs of

liver disease [26]. The American Society for Clinical

Oncology (ASCO) subsequently issued a provisional clin-

ical opinion in 2010 in response to the CDC recommen-

dations stating that there was insufficient evidence to

support routine HBV screening for all cancer patients who

are about to or are already receiving immunosuppressive or

cytotoxic therapy. ASCO recommended that (1) physicians

may exercise clinical judgment in the decision for HBV

screening specifically for high risk populations including

those receiving hematopoietic stem cell transplantation or

rituximab, and (2) testing should include HBsAg, and in

some populations, HBcAb, but there is no evidence to

support testing for HbsAb [27]. The American Association

for the Study of Liver Diseases (AASLD) recommends that

patients needing immunosuppressive therapy be screened

for HBV infection with HBsAg and HbsAb. Patients at

high risk for HBV, (i.e., patients from countries with high

or intermediate prevalence of HBV, illicit drug use, history

of sexually transmitted diseases, among others) should also

have their HBcAb checked [12].

The variability in recommendations for HBV screening

also extends to clinical trials. Current ongoing trials of

everolimus in various tumor types differ in their recom-

mendations for HBV screening (Table 2). Some trials

provide detailed criteria about which patients are at high

risk and therefore should be screened [28, 29]: some

exclude patients with chronic active or persistent hepatitis

[28–31] and yet, others do not include any hepatitis history

or screening in the eligibility criteria [32–35]. In addition,

the screening recommendations for HBV also differ within

breast cancer trials evaluating everolimus [31, 33–35].

These differing recommendations do not provide clear

guidelines for physicians regarding which and how patients

should be screened for HBV.

In April 2009, an expert panel of 11 physicians and

clinical nurses met to discuss the management of selected

adverse events associated with everolimus use for treat-

ment of metastatic renal cell carcinoma and the panel

recommended prophylactic therapy for both HBsAg-posi-

tive patients and HBcAb-positive patients to avoid HBV

reactivation [36]. The panel recommends close monitoring

of the HBV DNA for patients with known HBV infection.

In regards to choice of antiviral prophylaxis, while lami-

vudine has been extensively used for a long time, there is

potential risk of developing resistance with lamivudine,

which may impair future benefit from second-line thera-

pies. New guidelines, therefore, recommend use of highly

potent nucleoside analogs, such as entecavir and tenofovir

Table 1 Cytotoxic agents associated with HBV reactivation

Alkylating agents Cyclophosphamide

Chlorambucil

Cisplatin

Temozolomide

Procarbazine

Alkaloids Vincristine

Vinblastine

Antimetabolites Cytarabine

Fluorouracil

Gemcitabine

Mercaptopurine

Methotrexate

Thioguanine

Monoclonal antibodies Rituximab

Alemtuzumab

Other cytotoxic agents Bleomycin

Docetaxel

Etoposide

Fludarabine

Mitomycin

Other Interferon

170 Breast Cancer Res Treat (2013) 141:167–172

123

that can suppress viral replication and minimize hepatic

damage and development of resistance [37].

In conclusion, the combination of everolimus and exe-

mestane has proven to be safe with significant improvement

in progression-free survival in patients with ER?, HER2-

negative metastatic breast cancer. However, we are still

learning about the various adverse events of everolimus.

There are no unified HBV screening guidelines for patients

treated with everolimus either on an FDA approved indica-

tion or on a clinical trial. Oncologists and patients should be

aware of this rare, but potentially fatal adverse event that can

be seen with everolimus therapy. Based on our experience

and due to the biologic plausibility of hepatitis reactivation

with everolimus, we advocate that physicians take a detailed

history about HBV risk factors, perform appropriate

screening, and consider preventive therapy for HBsAg-

positive and HBcAb-positive patients under the guidance of

gastroenterology/hepatology experts.

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Table 2 Discrepancies in screening recommendations for HBV in select everolimus trials

Metastatic urothelial carcinoma [28] II NCT00805129 • Testing hepatitis B viral load and serologies for patients from

Asia, Africa, Central and South America, Eastern Europe, Spain,

Portugal or Greece and those with any risk factors: known or

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1990, current or prior IV drug users, current or prior dialysis,

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• Patients with liver disease (cirrhosis, chronic active hepatitis or

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Advanced neuroendocrine tumors of

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III RADIANT-4;

NCT01524783

• No recommendations for screening.

• Patients with liver disease such as cirrhosis, decompensated liver

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positive HBsAg, quantifiable HCV–RNA) are excluded.

ER?, HER2 negative locally advanced,

recurrent or metastatic breast cancer

[35]

II BOLERO-6;

NCT01783444

• No recommendations for screening.

Hormone receptor positive and HER2-

negative breast cancer in adjuvant

setting [31]

III South west oncology group

(SWOG) 1207;

NCT01674140

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• Patients with known hepatitis are not eligible.

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