Beruflich Dokumente
Kultur Dokumente
The Breast
journal homepage: www.elsevier.com/brst
Original article
a r t i c l e i n f o a b s t r a c t
Article history: Background: Chemotherapy has greatly improved the prognosis of breast cancer patients. However, it
Received 2 August 2017 may also result in undesirable side effects such as hepatitis virus reactivation. Little information is
Accepted 5 August 2017 available on the liver toxicity of chemotherapy and targeted therapy for breast cancer patients with
hepatitis virus (HBV/HCV) infection.
Methods: We performed a retrospective survey of 835 patients diagnosed with breast cancer between
Keywords:
January 2010 and December 2015 at our institution. All patients had been screened for HBV/HCV
Hepatitis B virus (HBV)
infection at the time of breast cancer diagnosis. We retrospectively investigated the toxicity of chemo-
Hepatitis C virus (HCV)
Breast cancer
therapy and the changes in HBV/HCV load based on a medical record review.
Chemotherapy Results: 52 patients with positive anti-HBV antibody test and 21 patients with positive anti-HCV anti-
HBV/HCV reactivation body tests received chemotherapy. 762 patients without HBV and HCV infection served as the control
Toxicity group. The morbidity of liver toxicity and disruptions in chemotherapy attributable to liver toxicity were
not significantly different among control group, HBV group and HCV groups (27.7% vs 34.6% vs 42.9%,
P ¼ 0.189 and 5.0% vs 9.6% vs 9.5%, P ¼ 0.173, respectively). No patients presented with HBV/HCV
reactivation.
Conclusion: Breast cancer patients with HCV can be treated with chemotherapy and targeted therapy
with trastuzumab. Breast cancer patients with HBV who accept antiviral therapy can be treated with
chemotherapy and targeted therapy with trastuzumab and patients can benefit from prophylactic
antiviral therapy before chemotherapy. However, a multidisciplinary cooperation and closely monitoring
liver function during the course of chemotherapy may benefit patients.
© 2017 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.breast.2017.08.001
0960-9776/© 2017 Elsevier Ltd. All rights reserved.
192 Y. Liu et al. / The Breast 35 (2017) 191e195
chemotherapy or lead to treatment failure [8e10]. Similarly, reac- 2.2. Qualitative tests for HBV DNA
tivation of HCV during chemotherapy has been reported among
HCV-infected patients with hematologic malignancies who have HBV DNA in serum was quantified using a commercially avail-
received rituximab, an anti-CD20 antigen that mainly inhibits B- able polymerase chain reaction approach (COBAS AmpliPrep/
cell function, therapy or combination chemotherapy [9,10]. It was COBAS TaqMan HCV Quantitative Test, v1; Roche Diagnostics, Basel,
reported that acute exacerbation of chronic HCV infection occurred Switzerland) with a quantification range of 20e69,000,000 IU/ml
in 6 of 9 (67%) episodes of HCV reactivation [10]. However, the (1.30e7.84 log10 IU/ml). This test's limit of sensitivity is 20 IU/ml.
immunosuppressive mechanisms of rituximab-based therapy for
hematologic malignancies and conventional chemotherapy for 2.3. Screening tests for antibodies to HCV
solid tumors are essentially different.
Despite guidelines for the management of HBV-infected pa- Abbott Architect i2000 chemiluminescence immunoassay sys-
tients during chemotherapy [2], limited data exist to support the tems (Abbott Laboratories, Abbott Park, IL, USA) were used to
use of chemotherapy to treat solid tumors in HCV-infected patients. screen for antibodies against HCV in accordance with the manu-
Although direct-acting antiviral agents (DAAs) have drastically facturer's instructions. The cutoff values used to determine positive
improved the prognosis of HCV infection [1], the course of treat- reactivity were established based on the manufacturer's recom-
ment is at least 12 weeks, and the interaction of DAAs with mendations. Samples with a signal/cutoff index (s/co) < 1.0 were
chemotherapy drugs has not been defined. regarded as negative, whereas samples with a signal/cutoff index
Overall, there is little information available on the effect of HCV (s/co) 1.0 were considered to be positive.
during chemotherapy for solid tumors and the influence of HCV
infection on the toxicity of chemotherapy [11] and the effect of 2.4. Qualitative tests for HCV RNA
preventive antiviral therapy on HBV-infected breast cancer patients
during chemotherapy. Therefore, the purpose of this study was to HCV RNA in serum was quantified using a commercially avail-
evaluate patient safety during chemotherapy in chronic hepatitis B able polymerase chain reaction approach (COBAS AmpliPrep/
or C virus infected patients with breast cancer. COBAS TaqMan HCV Quantitative Test, v1; Roche Diagnostics, Basel,
Switzerland) with a quantification range of 15e69,000,000 IU/ml
(1.18e7.84 log10 IU/ml). This test's limit of sensitivity is 15 IU/ml.
2. Patients and methods
2.5. Assessment of ER, PR and HER2 status
We performed a retrospective survey of 835 patients diagnosed
with breast cancer at the Third Affiliated Hospital of Sun Yat-sen ER and PR status were assessed by immunohistochemistry
University between January 2010 and December 2015. All pa- (IHC). HER-2 status was evaluated by IHC and/or fluorescence in
tients had been screened for HBV and HCV serology based on the situ hybridization (FISH).
presence of HBsAg and anti-HCV antibodies. We identified 52 pa- A semi-quantitative histochemical score was used to evaluate
tients who were positive for HBsAg and 21 patients who were the results of ER and PR staining according to the system estab-
positive for anti-HCV antibodies; all of these patients received lished by Allred et al. [12]. This system considers both the propor-
chemotherapy, including cytotoxic agents with or without trastu- tion and intensity of stained cells. Tumor cells with a total score of
zumab. We assigned 762 patients without HBV and HCV infection 3e8 were considered positive, whereas those with a total score less
to be the control group. The exclusion criteria included patients than 3 were considered negative.
who had decompensated liver disease; those who had not been HER-2 membranous staining was evaluated as 0 if no cells
treated with prophylactic antiviral therapy against HBV according showed staining; as 1 if incomplete, faint staining was present in
to the guideline [2,3]. We retrospectively investigated patients' >10% of cells; as 2 if complete, moderate staining was present in
characteristics including age, tumor histology, hormone receptor >10% of cells; and as 3 if complete, strong staining was present in
status (estrogen receptor (ER) and/or progesterone receptor (PR)), >10% of cells [13].
human epidermal growth factor receptor 2 (HER-2)/neu status For the FISH assay, we used a PathVysion HER-2 DNA Probe Kit
(according to immunohistochemistry and/or fluorescent in situ (Vysis Inc., Downers Grove, IL, USA). According to the ASCO/CAP
hybridization), baseline aspartate aminotransferase (AST) and guidelines for HER2 testing in breast cancer [14], the number of
alanine aminotransferase (ALT) levels, total bilirubin (TBIL), pro- HER2 gene signals and the number of chromosome 17 centromere
thrombin time (PT), changes in HBV load (in the HBV infected pa- (CEP17) signals per nucleus were counted for 20 tumor cells. The
tients), changes in HCV load (in the HCV infected patients), type of her-2 gene status was scored as the ratio between HER-2 red signals
chemotherapy and the toxicities of chemotherapy based on a re- and CEP17 green signals. A HER-2/CEP17 ratio >2.2 was interpreted
view of patients' medical records. as positive for gene amplification, whereas a HER-2/CEP17 ratio
This research was approved by ethics committee of the third <1.8 was defined as negative for gene amplification.
affiliated hospital of Sun Yat-sen University. Overall, samples were considered positive for HER-2 in cases in
which the IHC was 3 þ or the IHC was 2 þ and the FISH signal was
amplified.
2.1. Screening tests for hepatitis B surface antigen (HBsAg)
2.6. Assessment of liver function
Abbott Architect i2000 chemiluminescence immunoassay sys-
tems (Abbott Laboratories, Abbott Park, IL, USA) were used to Data of AST, ALT, TBIL and PT at baseline, during chemotherapy
screen for HBsAg in accordance with the manufacturer's in- and three months after completion chemotherapy were collected
structions. The cutoff values used to determine positive reactivity and assessed by Common Terminology Criteria for Adverse Events
were established based on the manufacturer's recommendations. (CTCAE) version 4.0. The severity of liver toxicity s was measured
Samples with a signal/cutoff index (s/co) < 1.0 were regarded as using a grade of 1 through 5. Grade 1 means mild; asymptomatic or
negative, whereas samples with a signal/cutoff index (s/co) 1.0 mild symptoms; clinical or diagnostic observations only; inter-
were considered to be positive. vention not indicated. Grade 2 means moderate; minimal, local or
Y. Liu et al. / The Breast 35 (2017) 191e195 193
noninvasive intervention indicated; limiting age-appropriate incidence of liver toxicity after chemotherapy among the different
instrumental ADL (Activities of Daily Living). Grade 3 means se- stage patients was highest in Stage IV patients (P ¼ 0.000 vs Stage I
vere or medically significant but not immediately life-threatening; patients, 0.001 vs Stage II patients, 0.025 vs Stage III patients). There
hospitalization or prolongation of hospitalization indicated; was no difference of the incidence of liver toxicity after chemo-
disabling; limiting self care ADL. Grade 4 means life-threatening therapy among patients of different stage in the HBV-infected
consequences; urgent intervention indicated. Grade 5 means group and the HCV-infected group (P ¼ 0.956 and 1.0 respec-
death related to adverse event. tively). But the numbers of Stage IV patients in these two groups
were few. 9 (25%) patients treated with Anthracycline based ther-
2.7. Reactivation of hepatitis virus apy, 33 (22.8%) patients treated with Taxane based therapy and 169
(29.1%) patients treated with Anthracycline þ Taxane based pre-
HBV reactivation was defined as an increase in HBV DNA level of sented with liver toxicity after chemotherapy in the control group.
tenfold or more when compared with the baseline level following 2 (50%) patients treated with Anthracycline based therapy, 5
chemotherapy or immunosuppressive therapy [15]. HCV reac- (38.5%) patients treated with Taxane based therapy and 11 (32.4%)
tivation was defined as an increase in HCV RNA level of tenfold or patients treated with Anthracycline þ Taxane based presented with
more when compared with the baseline level following chemo- liver toxicity after chemotherapy in HBV-infected group. 1 (50%)
therapy or immunosuppressive therapy [10]. patients treated with Anthracycline based therapy, 2 (33.3%) pa-
tients treated with Taxane based therapy and 6 (46.2%) patients
2.8. Statistical analyses treated with Anthracycline þ Taxane based presented with liver
toxicity after chemotherapy in HCV-infected group. There was no
IBM SPSS version 19.0 (IBM, Armonk, NY, USA) was employed to difference of the incidence of liver toxicity after chemotherapy
perform statistical analyses. The baseline demographic and clinical among patients treated with different chemotherapeutic regimens
characteristics are presented as percentages or as mean values with in the three groups (P ¼ 0.289, 0.719 and 1.0 respectively). Among
standard deviation (SD). Statistical significance was evaluated using the patients with liver toxicity in the three groups, there was no
the c2 test (Fisher's exact test) for categorical variables and the t- difference of the proportion of the four stages (P ¼ 0.315) and the
test or ManneWhitney U test for numerical variables; differences proportion of the different chemotherapeutic regimens (P ¼ 0.126)
were deemed significant when P < 0.05. (Table 3).
3. Results
Table 1
Patients and tumor characteristics are shown in Table 1. All Baseline characteristics of the patients.
(100%) of the patients were female, and no association between Control HBV-infected HCV-infected
age, clinical stage, tumor grade, or chemotherapy regimen was group group group
detected (P > 0.05). ALT and AST levels were higher in the HBV-
Total No. of patients 762 52 21
infected group and HCV-infected group compared to the control No. of females 762 (100%) 52 (100%) 21 (100%)
group. TBIL levels were higher in the HCV-infected group compared Age (years) 49.3 ± 10.3 47.3 ± 10.6 46.3 ± 11.2
to the control group. PT was longer in the HBV-infected group ALT 20.1 ± 6.6 27.3 ± 19.6* 35.7 ± 14.5*#
compared to the control group. Before receiving any chemotherapy, AST 21.6 ± 5.4 28.4 ± 18.3* 32.7 ± 11.8*
TBIL 12.1 ± 3.8 13.5 ± 5.4 15.3 ± 6.9*
8 (15.4%) and 4 (19.0%) patients had abnormal liver function in the PT 12.8 ± 0.6 13.3 ± 1.0* 13.1 ± 1.0
HBV-infected group and the HCV-infected group, respectively. No Abnormal liver function 0 8(15.4%) 4 (19.0%)
patients showed evidence of decompensated liver disease or (ALT>1ULN)
cirrhosis before the initiation of systemic chemotherapy. HBV DNA/HCV RNA (IU/ml e 6.6 ± 7.0 5.5 ± 1.9
log10)
On day 1 of each cycle of chemotherapy, HBV DNA, HCV RNA
Stage
quantitation was performed, and clinical signs and symptoms were I 144 (18.9%) 18 (34.6%) 5 (23.8%)
monitored in all patients. The HBV DNA level after completing II 508 (66.7%) 27 (51.9%) 13 (61.9%)
chemotherapy was lower than baseline. The average HBV DNA level III 73 (9.6%) 4 (7.7%) 2 (9.5%)
was 6.6 ± 7.0 IU/ml log10 before the initiation of chemotherapy and IV 37 (4.8%) 3 (5.8%) 1 (4.8%)
Tumor pathology
3.2 ± 3.8 IU/ml log10 (P ¼ 0.000) after completing chemotherapy. Histology
No patients presented with HBV reactivation. The average HCV RNA Invasive ductal carcinoma 617 (81%) 41 (78.8%) 16 (76.2%)
level was 5.5 ± 1.9 IU/ml log10 before the initiation of chemo- Noninvasive ductal 145 (19%) 11 (21.2%) 5 (23.8%)
therapy and 5.6 ± 2.0 IU/ml log10 (P ¼ 0.163) after completing carcinoma
Immunohistochemistry
chemotherapy. No patients presented with HCV reactivation. A total
ER status
of 238 (28.5%) patients in the study cohort presented with liver Negative 218 (28.6%) 19 (36.5%) 8 (38.1%)
toxicity including 211 (27.7%) patients in the control group, 18 Positive 544 (71.4%) 33 (63.5%) 13 (61.9%)
(34.6%) patients in the HBV-infected group, and 9 (42.9%) patients PR status
in the HCV-infected group. A total of 45 (5.4%) including 38 (5.0%) Negative 218 (28.6%) 21 (40.4%) 9 (42.9%)
Positive 544 (71.4%) 31 (59.6%) 12 (57.1%)
patients in the control group 5 (9.6%) patients in the HBV-infected HER-2 status
group, and 2 (9.5%) patients in the HCV-infected group underwent Negative 508 (66.7%) 42 (80.8%) 13 (61.9%)
disruptions in chemotherapy including dose reductions or dose Positive 254 (33.3%) 10 (19.2%) 8 (38.1%)
delays in chemotherapy attributable to liver toxicity. However, the Chemotherapeutic regimen(s)
Anthracycline based 36 (4.7%) 4 (7.7%) 2 (9.5%)
morbidity of liver toxicity and disruptions in chemotherapy
Taxane based 145 (19.0%) 13 (25%) 6 (28.6%)
attributable to liver toxicity were not significantly different among Anthracycline þ Taxane 580 (76.2%) 34 (65.4%) 13 (61.9%)
three groups (P ¼ 0.189 and 0.173, respectively) (Table 2). based
In the control group, 32 (22.2%) Stage I patients, 136 (26.7%) Others 1 (0.1%) 1 (9.6%) 0
Stage II patients, 23 (31.5%) Stage III patients and 20 (54.1%) Stage IV Trastuzumab therapy 127 (16.7%) 8 (15.4%) 4 (19.0%)
patients presented with liver toxicity after chemotherapy. The *P < 0.05 (VS control group), #P < 0.05 (VS HBV-infected group).
194 Y. Liu et al. / The Breast 35 (2017) 191e195
Table 2 were not different in breast cancer patients with or without HCV
Morbidity of the three groups during the study period. infection. ALT and AST levels, markers of liver function, were higher
Control HBV-infected HCV-infected in the HCV-infected group than the control group. However, during
group group group chemotherapy, no HCV reactivation occurred, and liver toxicity
Occurrence of hepatitis e 0 0 morbidity and disruptions in chemotherapy were not significantly
virus reactivation different in breast cancer patients with or without HCV infection.
Occurrence of liver toxicity These findings indicate that cytotoxic chemotherapy is not inter-
Total No. of patients 211 (27.7%) 18 (34.6%) 9 (42.9%)
fered with HCV reactivation in breast cancer patients with HCV
Grade 1 141 (18.5%) 11 (21.2%) 6 (28.6%)
Grade 2 58 (7.6%) 4 (7.7%) 1 (4.8%) infection. These findings support that cytotoxic therapy is feasible
Grade 3 11 (1.5%) 2 (3.8%) 2 (9.5%) for breast cancer patients with HCV infection.
Grade 4 1 (0.1%) 1 (1.9%) 0 Recently, some studies have reported that viral replication is a
Disruptions of chemotherapy 38 (5.0%) 5 (9.6%) 2 (9.5%)
major problem for cancer patients undergoing chemotherapy,
especially therapy with monoclonal antibodies. For example, rit-
uximab, a chimeric mouse-human antibody that binds to CD20
Table 3 antigens, can result in the elevation of transaminase and can lead to
Characteristics of Patients with liver injury after chemotherapy.
HBV and HCV reactivation in patients with lymphoma [19e21].
Control HBV-infected HCV-infected P Trastuzumab, a monoclonal antibody directed against the extra-
group group group cellular domain of HER-2, improves survival and quality of life in
Age (years) 54.3 ± 10.2 48.2 ± 10.2 50.0 ± 9.1 women with HER-2-positive breast cancer [22,23]. However, there
Stage 0.315 is little information on whether the use of trastuzumab reactivates
I 32 (22.2%) 7 (38.9%) 2 (40%)
HBV and HCV. Levaggi A et al. reported that the increase in trans-
II 136 (26.7%) 9 (33.3%) 6 (46.2%)
III 23 (31.5%) 1 (25%) 1 (50%) aminases resulted in discontinuation of trastuzumab treatment in
IV 20 (54.1%) 1 (33.3%) 0 2.2% HCV-infected breast cancer patients [18]. In our study, 8
Chemotherapeutic 0.126 (38.1%) patients with HCV and 4 (19.0%) patients underwent tras-
regimen(s) tuzumab therapy when 10 (19.2%) patients with HCV had HER-2
Anthracycline based 9 (25%) 2 (50%) 1 (50%)
Taxane based 33 (22.8%) 5 (38.5%) 2 (33.3%)
positive breast cancer and 8 (15.4%) patients underwent trastuzu-
Anthracycline þ Taxane 169 (29.1%) 11 (32.4%) 6 (46.2%) mab therapy. No clinically meaningful increase in liver enzymes or
based change in HCV-RNA level or HBV-DNA level was observed in breast
Others 0 0 0 cancer patients receiving trastuzumab therapy, suggesting that
Trastuzumab therapy 4 (3.1%) 0 0
trastuzumab therapy may be safe for breast cancer patients with
HCV or HBV infection.
In addition, we found that the incidence of liver toxicity after
4. Discussion chemotherapy among the different stage patients was highest in
Stage IV patients. These may contribute to the occurrence of liver
Reactivation of hepatitis virus may lead to a hepatitis flare or metastasis of breast cancer or bad performance status. Stage IV
liver failure, which may reduce the effectiveness of chemotherapy breast cancer patients should monitor liver function closely during
or even lead to treatment failure [8e10]. Reactivation of HBV and the course of chemotherapy. The incidence of liver toxicity after
the effects of prophylactic antiviral therapy have been previously chemotherapy was no different among the patients treated with
studied in breast cancer patients [8,15,16]. In our study, HBV- different chemotherapic regimens such as Anthracycline based
infected breast cancer patients had started antiviral therapy therapy, Taxane based therapy and Anthracycline þ Taxane based
before the diagnosis of breast cancer or started prophylactic anti- therapy. There is not any correlation between liver toxicity/therapy
viral therapy before chemotherapy according to the guidelines. The disruptions and chemotherapic regimens received.
morbidity of liver toxicity and disruptions in chemotherapy Nonetheless, our retrospective study is too limited to obtain a
attributable to liver toxicity were not significantly different be- definite conclusion on the safety of chemotherapy for breast cancer
tween breast cancer patients with or without HBV infection. The patients with HCV, and additional prospective large-scaled in-
HBV viral load was lower after chemotherapy which may attribute vestigations are warranted.
to the antiviral therapy during chemotherapy. Prophylactic antiviral
therapy can prevent HBV reactivation and reduce the HBV viral load 5. Conclusion
in breast cancer patients with HBV infection in chemotherapy and
patients can benefit from that. In all, our findings indicate that (1) breast cancer patients with
Compared to patients with HBV, few data are available on the HCV can be treated with chemotherapy and targeted therapy with
management of cancer patients with HCV infection. The clinical trastuzumab, (2) breast cancer patients with HBV who accept
impact of HCV infection on patients undergoing chemotherapy antiviral therapy can be treated with chemotherapy and targeted
remains poorly characterized. therapy with trastuzumab and patients can benefit from prophy-
Miura Y et al. reported that no clinically meaningful changes in lactic antiviral therapy before chemotherapy, (3) stage IV breast
HCV-RNA viral load in breast cancer patients who received cyto- cancer patients were vulnerable to liver toxicity during chemo-
toxic chemotherapy and/or trastuzumab [17]. But they did not therapy. Considering that liver injury may exist prior to the initia-
investigate the situation of uninfected breast cancer patients and tion of chemotherapy in breast cancer patients with hepatitis virus
disruptions in chemotherapy attributable to liver injury. Levaggi A infection, it is critical to seek multidisciplinary cooperation before
et al. reported that the incidence of liver injury of HBV or HCV the initiation of cytotoxic chemotherapy to assess the risk to benefit
infected breast cancer patients and HBV or HCV uninfected breast ratio of chemotherapy. As liver toxicity associated with chemo-
cancer patients was similar [18]. But they did not investigate HCV- therapy drugs and liver toxicity injury occurred during chemo-
RNA. In our study, we found that chemotherapy rarely caused HCV therapy treatment, it is also important to monitor liver function
reactivation in breast cancer patients with HCV infection. At base- closely during the course of chemotherapy especially in Stage IV
line, the tumor characteristics and the chemotherapeutic regimens patients.
Y. Liu et al. / The Breast 35 (2017) 191e195 195