Published Ahead of Print on May 12, 2014 as 10.1200/JCO.2013.49.8543 The latest version is at http://jco.ascopubs.org/cgi/doi/10.1200/JCO.2013.49.8543
JOURNAL OF CLINICAL ONCOLOGY
Nodular Regenerative Hyperplasia After Treatment With Trastuzumab Emtansine Introduction Trastuzumab emtansine (T-DM1) is a novel antibody-drug conjugate consisting of three components: trastuzumab, a recombinant antiepidermal growth factor receptor 2 (HER2) monoclonal antibody; thioether linker; and mertansine (DM1), a maytansinoid.1 The trastuzumab moiety of this antibody-drug conjugate binds to HER2 on tumor cell surfaces and on internalization, the DM1 moiety is released and binds to tubulin, thereby disrupting microtubule assembly/disassembly dynamics, resulting in cell-cycle arrest and cell death.1 Pharmacokinetic studies reveal complete proteolysis of the polypeptide backbone of the antibody component to its constituent amino acids, resulting in lysine-linker-DM1 inside the target cell.1,2 This major metabolite was reported to have low cytotoxic potency toward hepatocytes because of inability to penetrate the hepatocyte via the charged groups of the lysine residue.2 Preclinical studies demonstrated generation of lysine-linker-DM1 in liver tissue, mild increase in liver enzymes, and minimal degeneration of hepatocytes in monkeys.3 Furthermore, the liver was believed to be immune to cytotoxic effects of tubulin-binding antimitotic agents, such as DM1, because the hepatocytes are fully differentiated and nondividing.4 This drug is currently undergoing evaluation through several phase II and phase III studies in patients with HER2-positive breast cancer. Recently, a large phase III clinical trial (An Open-Label Study of Trastuzumab Emtansine [T-DM1] Versus Capecitabine ⫹ Lapatinib in Patients With HER2Positive Locally Advanced or Metastatic Breast Cancer [EMILIA]) reported an improvement in progression-free and overall survival with T-DM1 when compared with the combination of lapatinib and capecitabine for patients who had experienced disease progression while receiving previous trastuzumab-based therapy. In this study, the T-DM1 arm had an incidence of AST elevation of 22.4%, ALT elevation of 16.9%, and thrombocytopenia of 28%, resulting in dose reduction or discontinuation.5 Here we report two heavily pretreated patients with metastatic breast cancer who received T-DM1– based regimens while participating in phase Ib/II clinical trials and developed noncirrhotic portal hypertension (NCPH) as a result of nodular regenerative hyperplasia (NRH). Case Reports Patient 1 is a 66-year-old woman who was initially diagnosed with estrogen receptor (ER) –negative, progesterone receptor (PR) –negative, HER2-positive infiltrating ductal carcinoma of the left breast in June 2001. She underwent left breast lumpectomy with axillary lymph node dissection followed by adjuvant chemotherapy and left chest wall radiation from 2001 to 2002. Because of recurrence, she underwent multiple chemotherapy regimens through October 2009 (Table 1). She was then enrolled onto a phase Ib/II clinical trial (A Journal of Clinical Oncology, Vol 32, 2014
D I A G N O S I S
I N
O N C O L O G Y
Study of Trastuzumab Emtansine [Trastuzumab-MCC-DM1, T-DM1] in Combination With Pertuzumab Administered to Patients With Human Epidermal Growth Factor Receptor 2 [HER2] –Positive Locally Advanced or Metastatic Breast Cancer Who Have Previously Received Trastuzumab) to receive T-DM1 3 mg/kg intravenously once every 3 weeks plus pertuzumab 840 mg intravenous loading dose once, followed by 420 mg intravenously once every 3 weeks, in October 2009. A baseline abdominal computed tomography (CT) scan revealed normal-appearing liver with no evidence of portal hypertension. Follow-up abdominal CT scans per protocol (Fig 1) revealed the development of ascites (arrows) from NCPH, without evidence of metastatic disease, after initiation of T-DM1. In January 2011, the patient presented with progressively worsening abdominal pain; physical examination findings revealed abdominal tenderness and ascites. Laboratory tests included platelet count of 125 k/L, AST of 84 U/L, ALT of 48 U/L, alkaline phosphatase of 400 U/L, total bilirubin of 1.1 mg/dL, albumin of 3.5 mg/dL, and international normalized ratio of 1.0. Serologic tests for acute and chronic viral hepatitis were negative. Autoimmune serologies were positive for antinuclear antibody (1:160) and smooth muscle antibody (1:40); serum immunoglobulins were not elevated. Abdominal paracentesis and analysis of ascites fluid revealed a serum ascites albumin gradient ⬎ 1.1 with a neutrophil count ⬎ 250 cells/L, indicating portal hypertensive ascites and spontaneous bacterial peritonitis. An ultrasound with Doppler imaging of the liver revealed patent hepatic vasculature with bidirectional flow. Transjugular liver biopsy with portal pressure measurements revealed a hepatic vein pressure gradient of 13 mmHg with wedge and free hepatic vein pressures of 28 mmHg and 15 mmHg, respectively. The liver biopsy showed centrilobular sinusoidal dilation and congestion with atrophy of the hepatic plates, best seen on the reticulin stain (Fig 2A) highlighting thinnedout plates (arrows) alternating with thickened plates (asterisks), creating a nodular hepatic parenchyma in the absence of inflammation and fibrosis. Immunohistochemical staining for endothelial marker CD34 (Fig 2B) showed diffuse staining of sinusoidal endothelial cells around the portal tract (arrows). A diagnosis of noncirrhotic portal hypertension as a result of nodular regenerative hyperplasia was established. T-DM1 and pertuzumab were discontinued in December 2010. Liver biochemical tests and platelet counts (Fig 3A) improved approximately 1 month after cessation of T-DM1 plus pertuzumab. A moderate right portal vein occlusive thrombus was noted in February 2011 and treated with daily therapeutic doses of enoxaparin. An abdominal CT scan (Fig 1) taken 5 months after T-DM1 cessation showed resolution of the patient’s ascites (arrows), and she currently remains ascites free. Patient 2 is a 50-year-old woman who was initially diagnosed with ER-negative, PR-negative, HER2-positive ductal carcinoma in situ of the left breast in 2001. She underwent bilateral mastectomy with immediate reconstruction. She was diagnosed with metastatic ductal carcinoma in the left axilla in 2003 and underwent multiple chemotherapy regimens through August 2010 (Table 1). The patient was © 2014 by American Society of Clinical Oncology
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Copyright 2014 by American Society of Clinical Oncology
1
Force et al
Table 1. Select Demographic Characteristics, Previous Chemotherapeutic Regimens, and Clinical Manifestations of Patients
Patient
Age at Diagnosis (years)
Patient 1
55
39
Time From Start of T-DM1 to NRH Diagnosis
Liver test abnormalities Thrombocytopenia Ascites Esophageal varices
15 months
Liver test abnormalities Ascites Hepatic encephalopathy
17 months
Liver test abnormalities Thrombocytopenia
Previous Chemotherapy Regimens 1. 2. 3. 4. 5.
Patient 2
Manifestations of Portal Hypertension
6. 7. 1. 2. 3.
Doxorubicin ⫹ carboplatin ⫹ paclitaxel Taxotere ⫹ trastuzumab Navelbine ⫹ trastuzumab Capecitabine ⫹ vincristine ⫹ fluorouracil ⫹ bevacizumab ⫹ trastuzumab Oxaliplatin ⫹ fluorouracil ⫹ bevacizumab ⫹ trastuzumab Gemcitabine ⫹ lapatinib Paclitaxel ⫹ trastuzumab ⫹ alvespimycin Paclitaxel, carboplatin, trastuzumab Paclitaxel, carboplatin, lapatinib Navelbine, trastuzumab
Symptoms That Resolved
Hepatic encephalopathy Portal vein thrombosis Liver test abnormalities Thrombocytopenia Esophageal varices
Abbreviations: NRH, nodular regenerative hyperplasia; TDM-1, trastuzumab emtansine.
the upper limit of normal, with associated thrombocytopenia of 146,000/L 7 months into the clinical trial (Fig 3B), but she was otherwise asymptomatic. A surveillance abdominal CT scan in November 2011 showed signs of portal hypertension without evidence of metastatic disease. Serologies for acute and chronic viral hepatitis were negative. Autoimmune serology was positive for antinuclear antibody (1:320) but negative for smooth muscle antibody. A percutaneous liver biopsy stained with reticulin (Fig 2C) showed compression of hepatic plates (arrows) alternating with thickened plates (asterisk), which suggested atrophy and regeneration, respectively. Immunohistochemical staining for the endothelial marker CD34 showed
enrolled onto a phase Ib clinical trial (Trastuzumab and Trastuzumab-MCC-DM1 Administered Intravenously and GDC0941 Administered Orally to Patients With HER2-Positive Metastatic Breast Cancer Who Have Progressed on Previous Trastuzumab-Based Therapy) to receive combination T-DM1 3 mg/kg intravenously once every 3 weeks plus GDC-0941 (a selective phosphatidylinositol 3-kinase inhibitor) 130 mg orally on days 1 through 14 every 3 weeks in August 2010. A baseline abdominal CT scan revealed hepatic steatosis with otherwise normal liver and no evidence of portal hypertension. After 1 month of experimental therapy, the patient developed elevated serum aminotransferases that progressively increased to twice
T-DM1 initiation October 2009
April 2010
October 2010
December 2010
January 2011
May 2011
T-DM1 cessation Fig 1. 2
© 2014 by American Society of Clinical Oncology
JOURNAL OF CLINICAL ONCOLOGY
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Diagnosis in Oncology
A 160 140 120 100 80 60 40 20
ALT AST Platelet count
250 T-DM1 discontinued (day 490)
200 150 100
1,000/µL
Units/Liter
A
50 0
0
100
200
300
400
500
600
700
Time Since T-DM1 Initiation (days) 140
250
T-DM1 discontinued (day 476)
Units/Liter
120
B
200
100 150
80 60
100
40
ALT AST Platelet count
20
1,000/µL
B
50 0
0
100
200
300
400
500
600
700
Time Since T-DM1 Initiation (days) Fig 3.
T-DM1 and GDC-0941, the patient’s liver tests (Fig 3B) improved, with eventual normalization. Subsequent follow-ups have shown no evidence of ascites or signs of liver decompensation, and her thrombocytopenia has resolved.
C
Fig 2.
patchy staining of endothelial cells away from the periportal areas. There was also evidence of steatohepatitis in the form of mild (10%) macrovesicular steatosis and rare ballooned hepatocytes with Mallory hyaline. The patient was diagnosed with noncirrhotic portal hypertension as a result of nodular regenerative hyperplasia. An upper endoscopy revealed small esophageal varices. T-DM1 and GDC-0941 were discontinued in December 2011. Within 1 month after cessation of www.jco.org
Discussion T-DM1– based regimens are promising and offer the potential for better efficacy with less toxicity in the treatment of HER2-positive breast cancer.5-8 However, studies have also revealed adverse events that resulted in dose reduction or discontinuation of the drug.5,8 Catabolic sites for T-DM1 include the liver and reticuloendothelial system, and elimination is through the fecal/biliary system, with 80% of eliminated TDM-1 found in the feces and 50% found in the bile.9 Adverse events, hepatotoxicity, and hematologic toxicity are therefore not unanticipated.10,11 Although in vitro studies assessing the cytotoxic potencies of oxidized maytansinoids toward several human carcinoma cell lines found oxidized maytansinoids to be far less potent than maytansine,12,13 a recent phase III trial revealed grade ⱖ 3 adverse events of thrombocytopenia (12.9%), elevated AST (4.3%), and elevated ALT (2.9%).5 This adverse effect profile is similar to that found in other patients with breast and advanced solid tumor cancers receiving T-DM1 in phase I/II clinical trials.6-8,14 The two patients presented in this report developed NCPH related to NRH after receiving a T-DM1– based regimen. The absence of competing etiologies, along with close temporal association of laboratory abnormalities on initiation of T-DM1 and normalization of these values after discontinuation of TDM-1 (dechallenge), suggests that T-DM1 was directly associated with development of NRH and NCPH. However, NRH occurred in the presence of T-DM1 combination therapy, and it is unclear whether the same phenomenon would transpire with T-DM1 monotherapy. The altered endothelial phenotype, © 2014 by American Society of Clinical Oncology
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3
Force et al
as evidenced by aberrant CD34 staining, has been previously reported with NRH.15 Numerous chemotherapeutic agents are associated with NRH, including oxaliplatin/fluorouracil (regimen 5, patient 1). However, liver toxicity and progression of NRH were noted only after our patients began a T-DM1– based regimen; thus, it is unlikely that previous chemotherapies directly induced NRH. Nonetheless, the heavy amount of chemotherapy pretreatment may have primed these particular individuals for further injury with the maytansinoid portion of T-DM1. Abdominal imaging and liver biopsies with immunohistochemical staining for HER2 (data not shown) did not reveal any evidence of hepatobiliary metastatic disease. There are no human data that suggest an association of pertuzumab or GDC-0941 with NRH, NCPH, or alterations in liver biochemical tests. We found one case report showing trastuzumab-induced hepatotoxicity in a patient with locally advanced ER/PR-positive and HER-positive breast cancer.16 Liver biopsy in this patient revealed mild portal inflammation and mild interface hepatitis. In conclusion, a high index of suspicion for drug-induced liver injury must be maintained in patients undergoing treatment with T-DM1 who develop liver test abnormalities or signs of portal hypertension. Similarly, the possibility of nodular regenerative hyperplasia should be entertained. The injury may occur within months of initiating therapy, especially if the patient has received previous chemotherapy. Early and accurate diagnosis is vital because both liver test abnormalities and noncirrhotic portal hypertension seem to be reversible on T-DM1 discontinuation.
Jeremy Force, Romil Saxena, Bryan P. Schneider, Anna M. Storniolo, George W. Sledge Jr, Naga Chalasani, and Raj Vuppalanchi Indiana University School of Medicine, Indiana University Health, Indianapolis, IN
ACKNOWLEDGMENT
We thank Laurie D. DeLeve, MD, PhD, Division of Gastrointestinal and Liver Diseases, Keck School of Medicine of the University of Southern California, for critical review and thoughtful suggestions. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
Although all authors completed the disclosure declaration, the following author(s) and/or an author’s immediate family member(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a “U” are those for which no compensation was received; those relationships marked with a “C” were compensated. For a detailed description of the disclosure categories, or for more information about ASCO’s conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment or Leadership Position: None Consultant or Advisory Role: Romil Saxena, Mochida Pharmaceutical (C); Bryan P. Schneider,
Genentech (C); Naga Chalasani, Merck (C), sanofi aventis (C), Salix (C), Abbott Molecular (C), Eli Lilly (C), Mochida Pharmaceutical (C); Raj Vuppalanchi, Genentech (C), Pfizer (C), Vertex Pharmaceuticals (C), Bristol-Myers Squibb (C) Stock Ownership: None Honoraria: None Research Funding: Bryan P. Schneider, Genentech; Anna M. Storniolo, Genentech; George W. Sledge Jr, Genentech; Naga Chalasani, Intercept Pharmaceuticals, Eli Lilly, Gilead Pharmaceuticals, GenFit Expert Testimony: None Patents, Royalties, and Licenses: None Other Remuneration: None REFERENCES 1. Girish S, Gupta M, Wang B, et al: Clinical pharmacology of trastuzumab emtansine (T-DM1): An antibody-drug conjugate in development for the treatment of HER2-positive cancer. Cancer Chemother Pharmacol 69:1229-1240, 2012 2. Sun X, Widdison W, Mayo M, et al: Design of antibody-maytansinoid conjugates allows for efficient detoxification via liver metabolism. Bioconjug Chem 22:728-735, 2011 3. Zheng B, Fuji RN, Elkins K, et al: In vivo effects of targeting CD79b with antibodies and antibody-drug conjugates. Mol Cancer Ther 8:2937-2946, 2009 4. Gupta S, Bhattacharyya B: Antimicrotubular drugs binding to vinca domain of tubulin. Mol Cell Biochem 253:41-47, 2003 5. Verma S, Miles D, Gianni L, et al: Trastuzumab emtansine for HER2positive advanced breast cancer. N Engl J Med 367:1783-1791, 2012 6. Burris HA 3rd, Rugo HS, Vukelja SJ, et al: Phase II study of the antibody drug conjugate trastuzumab-DM1 for the treatment of human epidermal growth factor receptor 2 (HER2) –positive breast cancer after prior HER2-directed therapy. J Clin Oncol 29:398-405, 2011 7. Krop IE, Beeram M, Modi S, et al: Phase I study of trastuzumab-DM1, an HER2 antibody-drug conjugate, given every 3 weeks to patients with HER2positive metastatic breast cancer. J Clin Oncol 28:2698-2704, 2010 8. Krop IE, LoRusso P, Miller KD, et al: A phase II study of trastuzumab emtansine in patients with human epidermal growth factor receptor 2–positive metastatic breast cancer who were previously treated with trastuzumab, lapatinib, an anthracycline, a taxane, and capecitabine. J Clin Oncol 30:3234-3241, 2012 9. Shen BQ, Bumbaca D, Saad O, et al: Catabolic fate and pharmacokinetic characterization of trastuzumab emtansine (T-DM1): An emphasis on preclinical and clinical catabolism. Curr Drug Metab 13:901-910, 2012 10. Henderson LA, Baynes JW, Thorpe SR: Identification of the sites of IgG catabolism in the rat. Arch Biochem Biophys 215:1-11, 1982 11. Wright A, Sato Y, Okada T, et al: In vivo trafficking and catabolism of IgG1 antibodies with Fc associated carbohydrates of differing structure. Glycobiology 10:1347-1355, 2000 12. Cassady JM, Chan KK, Floss HG, et al: Recent developments in the maytansinoid antitumor agents. Chem Pharm Bull (Tokyo) 52:1-26, 2004 13. Remillard S, Rebhun LI, Howie GA, et al: Antimitotic activity of the potent tumor inhibitor maytansine. Science 189:1002-1005, 1975 14. Beeram M, Krop IE, Burris HA, et al: A phase 1 study of weekly dosing of trastuzumab emtansine (T-DM1) in patients with advanced human epidermal growth factor 2-positive breast cancer. Cancer 118:5733-5740, 2012 15. Foster JM, Litwin A, Gibbs JF, et al: Diagnosing regenerative nodular hyperplasia, the “great masquerader” of liver tumors. J Gastrointest Surg 10:727733, 2006 16. Srinivasan S, Parsa V, Liu CY, et al: Trastuzumab-induced hepatotoxicity. Ann Pharmacother 42:1497-1501, 2008
DOI: 10.1200/JCO.2013.49.8543; published online ahead of print at www.jco.org on April 28, 2014 ■ ■ ■
4
© 2014 by American Society of Clinical Oncology
JOURNAL OF CLINICAL ONCOLOGY
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JOURNAL OF CLINICAL ONCOLOGY
Nodular Regenerative Hyperplasia After Treatment With Trastuzumab Emtansine Introduction Trastuzumab emtansine (T-DM1) is a novel antibody-drug conjugate consisting of three components: trastuzumab, a recombinant antiepidermal growth factor receptor 2 (HER2) monoclonal antibody; thioether linker; and mertansine (DM1), a maytansinoid.1 The trastuzumab moiety of this antibody-drug conjugate binds to HER2 on tumor cell surfaces and on internalization, the DM1 moiety is released and binds to tubulin, thereby disrupting microtubule assembly/disassembly dynamics, resulting in cell-cycle arrest and cell death.1 Pharmacokinetic studies reveal complete proteolysis of the polypeptide backbone of the antibody component to its constituent amino acids, resulting in lysine-linker-DM1 inside the target cell.1,2 This major metabolite was reported to have low cytotoxic potency toward hepatocytes because of inability to penetrate the hepatocyte via the charged groups of the lysine residue.2 Preclinical studies demonstrated generation of lysine-linker-DM1 in liver tissue, mild increase in liver enzymes, and minimal degeneration of hepatocytes in monkeys.3 Furthermore, the liver was believed to be immune to cytotoxic effects of tubulin-binding antimitotic agents, such as DM1, because the hepatocytes are fully differentiated and nondividing.4 This drug is currently undergoing evaluation through several phase II and phase III studies in patients with HER2-positive breast cancer. Recently, a large phase III clinical trial (An Open-Label Study of Trastuzumab Emtansine [T-DM1] Versus Capecitabine ⫹ Lapatinib in Patients With HER2Positive Locally Advanced or Metastatic Breast Cancer [EMILIA]) reported an improvement in progression-free and overall survival with T-DM1 when compared with the combination of lapatinib and capecitabine for patients who had experienced disease progression while receiving previous trastuzumab-based therapy. In this study, the T-DM1 arm had an incidence of AST elevation of 22.4%, ALT elevation of 16.9%, and thrombocytopenia of 28%, resulting in dose reduction or discontinuation.5 Here we report two heavily pretreated patients with metastatic breast cancer who received T-DM1– based regimens while participating in phase Ib/II clinical trials and developed noncirrhotic portal hypertension (NCPH) as a result of nodular regenerative hyperplasia (NRH). Case Reports Patient 1 is a 66-year-old woman who was initially diagnosed with estrogen receptor (ER) –negative, progesterone receptor (PR) –negative, HER2-positive infiltrating ductal carcinoma of the left breast in June 2001. She underwent left breast lumpectomy with axillary lymph node dissection followed by adjuvant chemotherapy and left chest wall radiation from 2001 to 2002. Because of recurrence, she underwent multiple chemotherapy regimens through October 2009 (Table 1). She was then enrolled onto a phase Ib/II clinical trial (A Journal of Clinical Oncology, Vol 32, 2014
D I A G N O S I S
I N
O N C O L O G Y
Study of Trastuzumab Emtansine [Trastuzumab-MCC-DM1, T-DM1] in Combination With Pertuzumab Administered to Patients With Human Epidermal Growth Factor Receptor 2 [HER2] –Positive Locally Advanced or Metastatic Breast Cancer Who Have Previously Received Trastuzumab) to receive T-DM1 3 mg/kg intravenously once every 3 weeks plus pertuzumab 840 mg intravenous loading dose once, followed by 420 mg intravenously once every 3 weeks, in October 2009. A baseline abdominal computed tomography (CT) scan revealed normal-appearing liver with no evidence of portal hypertension. Follow-up abdominal CT scans per protocol (Fig 1) revealed the development of ascites (arrows) from NCPH, without evidence of metastatic disease, after initiation of T-DM1. In January 2011, the patient presented with progressively worsening abdominal pain; physical examination findings revealed abdominal tenderness and ascites. Laboratory tests included platelet count of 125 k/L, AST of 84 U/L, ALT of 48 U/L, alkaline phosphatase of 400 U/L, total bilirubin of 1.1 mg/dL, albumin of 3.5 mg/dL, and international normalized ratio of 1.0. Serologic tests for acute and chronic viral hepatitis were negative. Autoimmune serologies were positive for antinuclear antibody (1:160) and smooth muscle antibody (1:40); serum immunoglobulins were not elevated. Abdominal paracentesis and analysis of ascites fluid revealed a serum ascites albumin gradient ⬎ 1.1 with a neutrophil count ⬎ 250 cells/L, indicating portal hypertensive ascites and spontaneous bacterial peritonitis. An ultrasound with Doppler imaging of the liver revealed patent hepatic vasculature with bidirectional flow. Transjugular liver biopsy with portal pressure measurements revealed a hepatic vein pressure gradient of 13 mmHg with wedge and free hepatic vein pressures of 28 mmHg and 15 mmHg, respectively. The liver biopsy showed centrilobular sinusoidal dilation and congestion with atrophy of the hepatic plates, best seen on the reticulin stain (Fig 2A) highlighting thinnedout plates (arrows) alternating with thickened plates (asterisks), creating a nodular hepatic parenchyma in the absence of inflammation and fibrosis. Immunohistochemical staining for endothelial marker CD34 (Fig 2B) showed diffuse staining of sinusoidal endothelial cells around the portal tract (arrows). A diagnosis of noncirrhotic portal hypertension as a result of nodular regenerative hyperplasia was established. T-DM1 and pertuzumab were discontinued in December 2010. Liver biochemical tests and platelet counts (Fig 3A) improved approximately 1 month after cessation of T-DM1 plus pertuzumab. A moderate right portal vein occlusive thrombus was noted in February 2011 and treated with daily therapeutic doses of enoxaparin. An abdominal CT scan (Fig 1) taken 5 months after T-DM1 cessation showed resolution of the patient’s ascites (arrows), and she currently remains ascites free. Patient 2 is a 50-year-old woman who was initially diagnosed with ER-negative, PR-negative, HER2-positive ductal carcinoma in situ of the left breast in 2001. She underwent bilateral mastectomy with immediate reconstruction. She was diagnosed with metastatic ductal carcinoma in the left axilla in 2003 and underwent multiple chemotherapy regimens through August 2010 (Table 1). The patient was © 2014 by American Society of Clinical Oncology
Downloaded from jco.ascopubs.org on November 13, 2015. For personal use only. No other uses without permission. Copyright © 2014 American Society of Clinical Oncology. All rights reserved.
Copyright 2014 by American Society of Clinical Oncology
1
Force et al
Table 1. Select Demographic Characteristics, Previous Chemotherapeutic Regimens, and Clinical Manifestations of Patients
Patient
Age at Diagnosis (years)
Patient 1
55
39
Time From Start of T-DM1 to NRH Diagnosis
Liver test abnormalities Thrombocytopenia Ascites Esophageal varices
15 months
Liver test abnormalities Ascites Hepatic encephalopathy
17 months
Liver test abnormalities Thrombocytopenia
Previous Chemotherapy Regimens 1. 2. 3. 4. 5.
Patient 2
Manifestations of Portal Hypertension
6. 7. 1. 2. 3.
Doxorubicin ⫹ carboplatin ⫹ paclitaxel Taxotere ⫹ trastuzumab Navelbine ⫹ trastuzumab Capecitabine ⫹ vincristine ⫹ fluorouracil ⫹ bevacizumab ⫹ trastuzumab Oxaliplatin ⫹ fluorouracil ⫹ bevacizumab ⫹ trastuzumab Gemcitabine ⫹ lapatinib Paclitaxel ⫹ trastuzumab ⫹ alvespimycin Paclitaxel, carboplatin, trastuzumab Paclitaxel, carboplatin, lapatinib Navelbine, trastuzumab
Symptoms That Resolved
Hepatic encephalopathy Portal vein thrombosis Liver test abnormalities Thrombocytopenia Esophageal varices
Abbreviations: NRH, nodular regenerative hyperplasia; TDM-1, trastuzumab emtansine.
the upper limit of normal, with associated thrombocytopenia of 146,000/L 7 months into the clinical trial (Fig 3B), but she was otherwise asymptomatic. A surveillance abdominal CT scan in November 2011 showed signs of portal hypertension without evidence of metastatic disease. Serologies for acute and chronic viral hepatitis were negative. Autoimmune serology was positive for antinuclear antibody (1:320) but negative for smooth muscle antibody. A percutaneous liver biopsy stained with reticulin (Fig 2C) showed compression of hepatic plates (arrows) alternating with thickened plates (asterisk), which suggested atrophy and regeneration, respectively. Immunohistochemical staining for the endothelial marker CD34 showed
enrolled onto a phase Ib clinical trial (Trastuzumab and Trastuzumab-MCC-DM1 Administered Intravenously and GDC0941 Administered Orally to Patients With HER2-Positive Metastatic Breast Cancer Who Have Progressed on Previous Trastuzumab-Based Therapy) to receive combination T-DM1 3 mg/kg intravenously once every 3 weeks plus GDC-0941 (a selective phosphatidylinositol 3-kinase inhibitor) 130 mg orally on days 1 through 14 every 3 weeks in August 2010. A baseline abdominal CT scan revealed hepatic steatosis with otherwise normal liver and no evidence of portal hypertension. After 1 month of experimental therapy, the patient developed elevated serum aminotransferases that progressively increased to twice
T-DM1 initiation October 2009
April 2010
October 2010
December 2010
January 2011
May 2011
T-DM1 cessation Fig 1. 2
© 2014 by American Society of Clinical Oncology
JOURNAL OF CLINICAL ONCOLOGY
Downloaded from jco.ascopubs.org on November 13, 2015. For personal use only. No other uses without permission. Copyright © 2014 American Society of Clinical Oncology. All rights reserved.
Diagnosis in Oncology
A 160 140 120 100 80 60 40 20
ALT AST Platelet count
250 T-DM1 discontinued (day 490)
200 150 100
1,000/µL
Units/Liter
A
50 0
0
100
200
300
400
500
600
700
Time Since T-DM1 Initiation (days) 140
250
T-DM1 discontinued (day 476)
Units/Liter
120
B
200
100 150
80 60
100
40
ALT AST Platelet count
20
1,000/µL
B
50 0
0
100
200
300
400
500
600
700
Time Since T-DM1 Initiation (days) Fig 3.
T-DM1 and GDC-0941, the patient’s liver tests (Fig 3B) improved, with eventual normalization. Subsequent follow-ups have shown no evidence of ascites or signs of liver decompensation, and her thrombocytopenia has resolved.
C
Fig 2.
patchy staining of endothelial cells away from the periportal areas. There was also evidence of steatohepatitis in the form of mild (10%) macrovesicular steatosis and rare ballooned hepatocytes with Mallory hyaline. The patient was diagnosed with noncirrhotic portal hypertension as a result of nodular regenerative hyperplasia. An upper endoscopy revealed small esophageal varices. T-DM1 and GDC-0941 were discontinued in December 2011. Within 1 month after cessation of www.jco.org
Discussion T-DM1– based regimens are promising and offer the potential for better efficacy with less toxicity in the treatment of HER2-positive breast cancer.5-8 However, studies have also revealed adverse events that resulted in dose reduction or discontinuation of the drug.5,8 Catabolic sites for T-DM1 include the liver and reticuloendothelial system, and elimination is through the fecal/biliary system, with 80% of eliminated TDM-1 found in the feces and 50% found in the bile.9 Adverse events, hepatotoxicity, and hematologic toxicity are therefore not unanticipated.10,11 Although in vitro studies assessing the cytotoxic potencies of oxidized maytansinoids toward several human carcinoma cell lines found oxidized maytansinoids to be far less potent than maytansine,12,13 a recent phase III trial revealed grade ⱖ 3 adverse events of thrombocytopenia (12.9%), elevated AST (4.3%), and elevated ALT (2.9%).5 This adverse effect profile is similar to that found in other patients with breast and advanced solid tumor cancers receiving T-DM1 in phase I/II clinical trials.6-8,14 The two patients presented in this report developed NCPH related to NRH after receiving a T-DM1– based regimen. The absence of competing etiologies, along with close temporal association of laboratory abnormalities on initiation of T-DM1 and normalization of these values after discontinuation of TDM-1 (dechallenge), suggests that T-DM1 was directly associated with development of NRH and NCPH. However, NRH occurred in the presence of T-DM1 combination therapy, and it is unclear whether the same phenomenon would transpire with T-DM1 monotherapy. The altered endothelial phenotype, © 2014 by American Society of Clinical Oncology
Downloaded from jco.ascopubs.org on November 13, 2015. For personal use only. No other uses without permission. Copyright © 2014 American Society of Clinical Oncology. All rights reserved.
3
Force et al
as evidenced by aberrant CD34 staining, has been previously reported with NRH.15 Numerous chemotherapeutic agents are associated with NRH, including oxaliplatin/fluorouracil (regimen 5, patient 1). However, liver toxicity and progression of NRH were noted only after our patients began a T-DM1– based regimen; thus, it is unlikely that previous chemotherapies directly induced NRH. Nonetheless, the heavy amount of chemotherapy pretreatment may have primed these particular individuals for further injury with the maytansinoid portion of T-DM1. Abdominal imaging and liver biopsies with immunohistochemical staining for HER2 (data not shown) did not reveal any evidence of hepatobiliary metastatic disease. There are no human data that suggest an association of pertuzumab or GDC-0941 with NRH, NCPH, or alterations in liver biochemical tests. We found one case report showing trastuzumab-induced hepatotoxicity in a patient with locally advanced ER/PR-positive and HER-positive breast cancer.16 Liver biopsy in this patient revealed mild portal inflammation and mild interface hepatitis. In conclusion, a high index of suspicion for drug-induced liver injury must be maintained in patients undergoing treatment with T-DM1 who develop liver test abnormalities or signs of portal hypertension. Similarly, the possibility of nodular regenerative hyperplasia should be entertained. The injury may occur within months of initiating therapy, especially if the patient has received previous chemotherapy. Early and accurate diagnosis is vital because both liver test abnormalities and noncirrhotic portal hypertension seem to be reversible on T-DM1 discontinuation.
Jeremy Force, Romil Saxena, Bryan P. Schneider, Anna M. Storniolo, George W. Sledge Jr, Naga Chalasani, and Raj Vuppalanchi Indiana University School of Medicine, Indiana University Health, Indianapolis, IN
ACKNOWLEDGMENT
We thank Laurie D. DeLeve, MD, PhD, Division of Gastrointestinal and Liver Diseases, Keck School of Medicine of the University of Southern California, for critical review and thoughtful suggestions. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
Although all authors completed the disclosure declaration, the following author(s) and/or an author’s immediate family member(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a “U” are those for which no compensation was received; those relationships marked with a “C” were compensated. For a detailed description of the disclosure categories, or for more information about ASCO’s conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment or Leadership Position: None Consultant or Advisory Role: Romil Saxena, Mochida Pharmaceutical (C); Bryan P. Schneider,
Genentech (C); Naga Chalasani, Merck (C), sanofi aventis (C), Salix (C), Abbott Molecular (C), Eli Lilly (C), Mochida Pharmaceutical (C); Raj Vuppalanchi, Genentech (C), Pfizer (C), Vertex Pharmaceuticals (C), Bristol-Myers Squibb (C) Stock Ownership: None Honoraria: None Research Funding: Bryan P. Schneider, Genentech; Anna M. Storniolo, Genentech; George W. Sledge Jr, Genentech; Naga Chalasani, Intercept Pharmaceuticals, Eli Lilly, Gilead Pharmaceuticals, GenFit Expert Testimony: None Patents, Royalties, and Licenses: None Other Remuneration: None REFERENCES 1. Girish S, Gupta M, Wang B, et al: Clinical pharmacology of trastuzumab emtansine (T-DM1): An antibody-drug conjugate in development for the treatment of HER2-positive cancer. Cancer Chemother Pharmacol 69:1229-1240, 2012 2. Sun X, Widdison W, Mayo M, et al: Design of antibody-maytansinoid conjugates allows for efficient detoxification via liver metabolism. Bioconjug Chem 22:728-735, 2011 3. Zheng B, Fuji RN, Elkins K, et al: In vivo effects of targeting CD79b with antibodies and antibody-drug conjugates. Mol Cancer Ther 8:2937-2946, 2009 4. Gupta S, Bhattacharyya B: Antimicrotubular drugs binding to vinca domain of tubulin. Mol Cell Biochem 253:41-47, 2003 5. Verma S, Miles D, Gianni L, et al: Trastuzumab emtansine for HER2positive advanced breast cancer. N Engl J Med 367:1783-1791, 2012 6. Burris HA 3rd, Rugo HS, Vukelja SJ, et al: Phase II study of the antibody drug conjugate trastuzumab-DM1 for the treatment of human epidermal growth factor receptor 2 (HER2) –positive breast cancer after prior HER2-directed therapy. J Clin Oncol 29:398-405, 2011 7. Krop IE, Beeram M, Modi S, et al: Phase I study of trastuzumab-DM1, an HER2 antibody-drug conjugate, given every 3 weeks to patients with HER2positive metastatic breast cancer. J Clin Oncol 28:2698-2704, 2010 8. Krop IE, LoRusso P, Miller KD, et al: A phase II study of trastuzumab emtansine in patients with human epidermal growth factor receptor 2–positive metastatic breast cancer who were previously treated with trastuzumab, lapatinib, an anthracycline, a taxane, and capecitabine. J Clin Oncol 30:3234-3241, 2012 9. Shen BQ, Bumbaca D, Saad O, et al: Catabolic fate and pharmacokinetic characterization of trastuzumab emtansine (T-DM1): An emphasis on preclinical and clinical catabolism. Curr Drug Metab 13:901-910, 2012 10. Henderson LA, Baynes JW, Thorpe SR: Identification of the sites of IgG catabolism in the rat. Arch Biochem Biophys 215:1-11, 1982 11. Wright A, Sato Y, Okada T, et al: In vivo trafficking and catabolism of IgG1 antibodies with Fc associated carbohydrates of differing structure. Glycobiology 10:1347-1355, 2000 12. Cassady JM, Chan KK, Floss HG, et al: Recent developments in the maytansinoid antitumor agents. Chem Pharm Bull (Tokyo) 52:1-26, 2004 13. Remillard S, Rebhun LI, Howie GA, et al: Antimitotic activity of the potent tumor inhibitor maytansine. Science 189:1002-1005, 1975 14. Beeram M, Krop IE, Burris HA, et al: A phase 1 study of weekly dosing of trastuzumab emtansine (T-DM1) in patients with advanced human epidermal growth factor 2-positive breast cancer. Cancer 118:5733-5740, 2012 15. Foster JM, Litwin A, Gibbs JF, et al: Diagnosing regenerative nodular hyperplasia, the “great masquerader” of liver tumors. J Gastrointest Surg 10:727733, 2006 16. Srinivasan S, Parsa V, Liu CY, et al: Trastuzumab-induced hepatotoxicity. Ann Pharmacother 42:1497-1501, 2008
DOI: 10.1200/JCO.2013.49.8543; published online ahead of print at www.jco.org on April 28, 2014 ■ ■ ■
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