- Email: [email protected]
Trastuzumab emtansine associated nodular regenerative hyperplasia: A case report and review of literature
Cancer Treatment Communications 5 (2016) 26–30
Contents lists available at ScienceDirect
Cancer Treatment Communications journal homepage: www.elsevier.com/locate/ctrc
Trastuzumab emtansine associated nodular regenerative hyperplasia: A case report and review of literature L.H. Prochaska, I. Damjanov, R.M. Ash, J.C. Olson, Q.J. Khan, P. Sharma n University of Kansas Medical Center, 2330 Shawnee Mission Parkway, Westwood, KS, USA
art ic l e i nf o
a b s t r a c t
Article history: Received 30 July 2015 Received in revised form 17 November 2015 Accepted 29 November 2015
Background: Trastuzumab emtansine (T-DM1), a novel drug-antibody conjugate, has shown promising activity in HER2-positive breast cancer and is the recommended agent of choice for second line therapy for advanced HER 2-positive breast cancer. Elevations in transaminase levels have been reported in up to 40% of patients treated with T-DM1 on phase I-III clinical studies. More serious hepatotoxicity can also result from this drug-antibody conjugate, but has been infrequently described in the literature. Case Presentation: Here we report a 73 year old female with previously untreated metastatic HER 2-positive breast cancer who developed nodular regenerative hyperplasia and noncirrhotic portal hypertension while on treatment with single agent T-DM1. Liver biopsy demonstrated nodular regenerative hyperplasia, bile duct injury, and portal fibrosis. Conclusion: A high index of suspicion for liver injury and NRH must be maintained for patients who develop liver test abnormalities and/or signs of portal hypertension during treatment with T-DM1. Abdominal imaging, liver biopsy, and prompt discontinuation of T-DM1 is recommended for patients with signs or symptoms of liver injury. & 2015 Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Keywords: Trastuzumab emtanisine Metastatic HER2-positive breast cancer Nodular regenerative hyperplasia Noncirrhotic portal hypertension
1. Background Trastuzumab emtansine (T-DM1) is a drug-antibody conjugate linking trastuzumab to emtansine by non-reducible thioester linker, 4-[N-maleimidomethyl] cyclohexane-1 carboxylate (MCC) [1]. Trastuzumab is a monoclonal antibody targeting the human epidermal growth factor receptor-2 (HER2) and emtansine (DM-1), a maytansine derivative, and is a cytotoxic agent that acts by microtubule inhibition. The drug-antibody conjugate binds the HER2 receptor and becomes internalized whereby DM-1 can then disrupt the microtubules and cause cell death and apoptosis [2]. T-DM1 was first studied in patients with advanced HER 2-positive breast cancer in 2010 in a phase I trial, where substantial clinical benefit was noted [3]. The most common adverse events related to T-DM1 that were noted in the phase I study were thrombocytopenia (54.2%) and elevated transaminases (41.7%). Abbreviations: T-DM1, Trastuzumab emtansine; MCC, 4-[N-maleimidomethyl] cyclohexane-1 carboxylate; HER2, human epidermal growth receptor-2; DM-1, emtansine; NRH, nodular regenerative hyperplasia; ER, estrogen receptor; PR, progesterone recepton; TCH, docetaxel, carboplatin, Herceptin chemotherapy regimen; NCPH, noncirrhotic portal hypertension n Corresponding author. E-mail address: [email protected] (P. Sharma).
Subsequent phase II and III trials continued to show promising activity of T-DM1 in patients with heavily pretreated HER 2-positive advanced breast cancer leading to FDA approval of T-DM1 in the second line setting for treatment of advanced HER-2 positive metastatic breast cancer [4–8]. Transaminase elevation has been a known and common side effect associated with T-DM1, with mild grade 1–2 abnormalities noted in 31.8% and grade Z3 abnormalities noted in 7.4% in an integrated safety analysis [9]. Serious hepatotoxicity, including portal hypertension [3], cirrhosis [7], and rare cases of nodular regenerative hyperplasia (NRH) [9,10] have been recently reported in patients treated with T-DM1 on clinical trials. Most of these prior reports of portal hypertension and NRH associated with T-DM1 occurred in patients that were heavily pretreated with chemotherapy and HER 2 targeted therapy. The heavy amount of chemotherapy pretreatment may have primed these particular individuals for further injury with the maytansinoid portion of T-DM1. There have been no reported cases of NRH with T-DM1 when used as a first line therapy in metastatic breast cancer patients outside of clinical trials. Here we report a patient with previously untreated metastatic HER 2-positive breast cancer who developed NRH resulting in noncirrhotic portal hypertension and biliary duct injury while on treatment with single agent T-DM1.
http://dx.doi.org/10.1016/j.ctrc.2015.11.008 2213-0896/& 2015 Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
L.H. Prochaska et al. / Cancer Treatment Communications 5 (2016) 26–30
2. Case presentation
T-DM1 discontinued
2 1.5
AST ALT
1
Alk phos Bili
0.5 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 Months post T-DM1 initiation
250 230 210 T-DM1 discontinued
190 K/UL
A 73-year-old female was diagnosed with locally advanced estrogen receptor (ER) positive, progesterone receptor (PR) negative, HER 2-positive (HER 2 FISH 4.2), stage IIIA (T3N2) left breast CA in January 2010. She received 6 cycles of neoadjuvant Docetaxel, Carboplatin, Herceptin (TCH) and underwent modified radical mastectomy. Following surgery, she completed 52 weeks of adjuvant Herceptin and was placed on adjuvant endocrine therapy with anastrazole. She was found to have new mediastinal and right supraclavicular adenopathy in March 2013 and biopsy of the supraclavicular lymph node confirmed HER-2 positive, ER/PR negative metastatic breast cancer. T-DM1 3.6 mg/kg was initiated in April 2013 for treatment of her newly diagnosed metastatic disease. This was chosen as first line therapy due to patient’s age and her desire to avoid toxicities of conventional chemotherapy. CT scan of the abdomen prior to starting T-DM1 showed hepatic steatosis with otherwise normal liver and no evidence of portal hypertension. CT imaging in June 2013 showed improvement in the mediastinal lymphadenopathy and mild fatty liver that was unchanged (Fig. 1). Over the next 12 months she continued on T-DM1 with good control of the mediastinal metastatic disease. Liver function tests (AST/ALT/Alkaline phosphatase) fluctuated during this time period but stayed o2.5X ULN (Fig. 2A). Grade 1 thrombocytopenia was also noted after starting TDM-1 with a nadir of 99,000 while on therapy (Fig. 2B). CT abdomen in June 2014 (15 months after starting T-DM1) showed morphologic evidence of chronic liver disease with nodularity and slight widening of the fissure for the ligamentum teres hepatis, along with splenomegaly and esophageal varices (Fig. 1). At that time, T-DM1 was discontinued and liver workup was pursued. Hepatitis panel, anti-mitochondrial antibodies, ANA, and alpha-1 antitrypsin were all negative. Anti smooth muscle antibody titer was minimally elevated at 20 (reference range o20). Liver biopsy was performed in September 2014. Pathology demonstrated nodule-like expansion of the liver cell cords compressing the peripheral hepatocytes, consistent with nodular regenerative hyperplasia (Fig. 3A). Reticulin stain (Fig. 3B) demonstrated compressed hepatocytes, further supporting the diagnosis of NRH. Changes consistent with biliary duct injury were also noted. The CK7 immunohistochemistry showed bile duct loss from the portal tracts with a “blush staining of hepatocytes”, indicative of biliary metaplasia (Fig. 3). Abdominal CT from November 2014 continued to show persistent liver disease and evidence of portal hypertension. Esophagogastroduodenoscopy performed in February 2015 due to the portal hypertension showed esophageal varices, requiring banding. Clinical or radiological ascites was not noted and the patient did not demonstrate any symptoms associated with portal hypertension. Laboratory studies after T-DM1 discontinuation
X upper limits of normal (ULN)
2.5
27
170 150
platelets
130 110 90 70 50 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 Months post T-DM1 initiation
Fig. 2. Liver function tests (A) and platelet levels (B) in relation to T-DM1 initiation and discontinuation.
demonstrated normalization of AST and ALT at 6 months (Fig. 2A). Alkaline phosphatase also improved and was less than 1.5X ULN at 9-month follow up. Platelets improved but had not normalized by 9-month follow up (Fig. 2B). Fig. 4 outlines the treatment history leading to development of NRH. Patient remains off all anticancer therapy and without evidence of active breast cancer at this time.
3. Discussion T-DM1 is a drug-antibody conjugate consisting of trastuzumab, emtansine, and a thioester linker that has shown very promising activity in advanced HER 2-positive breast cancer. T-DM1 is an appealing treatment option for metastatic HER 2-positive breast cancer as it is devoid of toxicities associated with conventional cytotoxic agents. Transaminase elevations and thrombocytopenia with T-DM1 are well known with grade 3 and 4 events in acceptable ranges for treatment of advanced breast cancer. Mild transaminase elevation are noted in 30-40% of patients on TDM-1 and do not require interruption in therapy. However, patients with durable responses who remain on T-DM1 for long periods may develop more serious
Fig. 1. CT imaging changes following T-DM1 initiation.
28
L.H. Prochaska et al. / Cancer Treatment Communications 5 (2016) 26–30
liver damage that goes unrecognized in the setting of persistent but mild LFT elevation. Nodular regenerative hyperplasia is a rare but serious complication of T-DM1 that has been reported in the literature, but never outside of a clinical trial. One case reported two patients on T-DM1 who developed noncirrhotic portal hypertension related to nodular regenerative hyperplasia [10] (Table 1). Both of these patients were on clinical trials, received TDM1 with other investigational agents, and had extensive prior treatment for metastatic disease. In an integrated toxicity analysis of six T-DM1 clinical trials, NRH was noted in 3 out of 884 patients (0.3%). All 3 patients developed portal hypertension and 1 patient died as a result of liver failure [9]. Our case reports a patient with previously untreated metastatic HER 2-positive breast cancer who developed NRH and asymptomatic noncirrhotic portal hypertension (NCPH) while on treatment with single agent T-DM1. To our knowledge, this is the first reported case of T-DM1 associated NRH in a non-clinical trial patient who received TDM-1 as first line treatment for metastatic HER 2-positive breast cancer. The risk of TDM-1 associated liver injury may be increased in patients with extensive prior treatment, but our case demonstrates that this risk is present even in patients who have not had any prior therapy for treatment of metastatic disease. The time from initiation of TDM-1 and NRH diagnosis in the above five patients ranged from 2 to 27 months and was greater than 12 months in 4 of the 5 previously reported cases. Our patient was diagnosed with NRH within a similar time frame, 15 months after initiation of T-DM1. Thus, chronicity of TDM-1 use seems to emerge as a potential risk factor for development of NRH. Age does not appear to relate given our relatively older patient (73 years) compared with younger patients (66 years and 50 years old) in one of the aforementioned trials [10]. Biological mechanisms that explain the link between chronicity of TDM-1 use and NRH are not clear and should be investigated further. It is possible that pre-existing fatty infiltration of liver increases the risk of NRH. Only two (of 5) previously reported cases of NRH provide information on the status of baseline liver function; one of which had hepatic steatosis prior to T-DM1 initiation. Interestingly, our patient also had CT evidence of mild fatty liver at baseline. It is known that fatty infiltration makes the liver more vulnerable to hepatocellular injury initiated by reactive oxygen species, which can be induced by drugs [11,12]. A direct correlation between hepatic steatosis and NRH has not been documented in the literature. NRH is characterized by hepatic parenchyma transformation into nodules with innumerable areas of focal regeneration demarcated by adjacent compressive, atrophic, degenerative, and circulatory effects [13]. This damage leads to NCPH, as seen in our patient and those in the literature. The intralobular fibrosis in response to the liver cell injury and loss of injured hepatocytes can
Fig. 3. Nodular regenerative hyperplasia (A) Hepatocytes form indistinct small nodules (arrows) compressing the surrounding cells. H&E 160. (B) Reticulin stain outlines the nodules and the compressed hepatocytes around them ( 160). (C) Immunohistochemical stain with antibodies to cytokeratin that stains selectively the bile ducts and ductules. The lower lobule shows a ductal reaction around a portal tract missing the primary duct (bottom part of the figure). In the upper lobule there is a “blush-like” staining of periportal hepatocytes undergoing ductal metaplasia ( 220). (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)
T-DM 1initiated
1/2010
6 cycles TCH
Diagnosed with stage III breast cancer ER+, HER2+
T-DM1 discontinued
Adjuvant Herceptin completed
8/2010
Adjuvant Anastrazole initiated
Modified radical mastectomy
3/2013
Diagnosed with metastatic breast cancer ER-, HER2+
4/2013
6/2014
9/2014
CT showed liver disease and portal hypertension
NRH diagnosed via liver biopsy
Fig. 4. Treatment history timeline leading to development of NRH.
L.H. Prochaska et al. / Cancer Treatment Communications 5 (2016) 26–30
29
Table 1 Summary of previously reported cases of NRH. Age
Line of therapy
Previous Treatment regimensa
Concomitant drugsb
Start of T-DM1 until NRH diagnosis
Time to LFT recovery
73c 55
First Eighth
None Pertuzumab
15 months 15 months
6 months 1 month
39
Fourth
No previous therapy in metastatic setting Doxorubicin þ carboplatinþ paclitaxel Taxotereþtrastuzumab Navelbineþ trastuzumab Capecitabine þvincristine þfluorouracil þ bevacizumab þ trastuzumab Oxaliplatin þ fluorouracil þbevacizumab þtrastuzumab Gemcitabine þ lapatinib Paclitaxelþ trastuzumabþalvespimycin Paclitaxelþ carboplatin þtrastuzumab Paclitaxelþ carboplatin þlapatinib Navelbineþ traztuzumab Unk Unk Unk
Pictilisib (GDC-0941)
17 months
2 months
3 months 27 months 15 months
Unk Unk Unk
Unk Unk Unk Unk Unk Unk a b c
In metastatic setting. Administered along with with T-DM1, LFT ¼ Liver Function tests, Unk ¼unknown. Current cases.
explain the AST and ALT elevations. One thing that could not be explained by NRH in our patient was the bile duct injury confirmed on liver biopsy. The bile ductular injury explains elevation in alkaline phosphatase and bilirubin noted in our patient, which were rarely elevated in the abovementioned reports. Given no obvious bile duct obstruction and the temporal association of alkaline phosphatase elevation and T-DM1 initiation/discontinuation in our patient, it is suspected that T-DM1 also contributed to this pathology. Despite the noted incidence of hepatic injury in patients treated with T-DM-1, the mechanism in which this occurs is still not clear. Internalization of T-DM1 into Fc-receptor-bearing Kupffer cells with subsequent release of free DM1 into the local microenvironment is one potential explanation. T-DM1 related hepatic injury due to low levels of free DM1 briefly observed in the systemic circulation after T-DM1 is another possibility [3]. Trastuzumab alone has only rarely been reported to cause elevated transaminases and there are no reports of single agent trastuzumab related NRH [14,15]. Trastuzumab in combination with chemotherapy has led to elevated transaminases (grade r2) in clinical trials, but it difficult to know if hepatotoxicity in this setting was chemotherapy or monoclonal antibody related [5]. Similarly, emtansine alone has not been documented to cause NRH, however it is well described that the liver plays an important role in degradation and detoxification of antibody-maytansinoid conjugates [16–18]. It is possible that hepatic injury may be more of a class effect since elevation in transaminase levels are not limited to the trastuzumab emtansine conjugate but have also been seen with other drug-antibody conjugates [19]. The mechanisms by which thrombocytopenia results from T-DM1 have been studied in the literature and is felt in large to be related to T-DM1-induced impairment of megakaryocyte differentiation [20], but liver damage leading to portal hypertension and splenic sequestration may also be playing a role in some patients. In conclusion, a high index of suspicion for drug-induced NRH must be maintained in patients undergoing treatment with TDM-1 and elevations in transaminase levels should be monitored closely. The frequent transaminase elevations noted in patients on treatment with T-DM1 may lead to under-investigation of other etiologies of the liver function test abnormalities, as was the case for our patient. Our patient was asymptomatic and further investigation including liver biopsy was undertaken only after radiologic evidence of portal hypertension was noted. We suggest that patients who continue on T-DM1 treatment for greater than 12 months and have grade 1 or 2 transaminitis should undergo a
regular evaluation for portal hypertension and NRH with appropriate imaging. Future research efforts should focus on early detection of NRH (prior to development of portal hypertension) and identifying risk factors associated with development of this liver injury.
4. Consent Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.
Competing interests The authors declare that they have no competing financial interests.
Authors' contributions LHP, ID, RMA, JCO, QJK, PS obtained the data LHP, ID, RMA, JCO, QJK, PS documented the case and LHP, ID, RMA, JCO, QJK, PS performed the literature search LHP, ID, RMA, JCO, QJK, PS contributed to the writing process LHP, ID, RMA, JCO, QJK, PS critically reviewed the data LHP, ID, RMA, JCO, QJK, PS contributed to the writing process All authors read and approved the final manuscript.
Acknowledgments None.
Appendix A. Supplementary material Supplementary data associated with this article can be found in the online version at http://dx.doi.org/10.1016/j.ctrc.2015.11.008. References [1] J.M. Baron, B.L. Boster, C.M. Barnett, Ado-trastuzumab emtansine (T-DM1): a
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novel antibody-drug conjugate for the treatment of HER2-positive metastatic breast cancer, J. Oncol. Pharm. Pract. 21 (2) (2015) 132–142. S. Girish, M. Gupta, B. Wang, D. Lu, I.E. Krop, C.L. Vogel, H.A. Burris Iii, P. M. LoRusso, J.H. Yi, O. Saad, 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 (5) (2012) 1229–1240. I.E. Krop, M. Beeram, S. Modi, S.F. Jones, S.N. Holden, W. Yu, S. Girish, J. Tibbitts, J.H. Yi, M.X. Sliwkowski, et al., Phase I study of trastuzumab-DM1, an HER2 antibody-drug conjugate, given every 3 weeks to patients with HER2-positive metastatic breast cancer, J. Clin. Oncol. 28 (16) (2010) 2698–2704. I.E. Krop, P. LoRusso, K.D. Miller, S. Modi, D. Yardley, G. Rodriguez, E. Guardino, M. Lu, M. Zheng, S. Girish, 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 (26) (2012) 3234–3241. S.A. Hurvitz, L. Dirix, J. Kocsis, G.V. Bianchi, J. Lu, J. Vinholes, E. Guardino, C. Song, B. Tong, V. Ng, et al., Phase II randomized study of trastuzumab emtansine versus trastuzumab plus docetaxel in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer, J. Clin. Oncol. 31 (9) (2013) 1157–1163. S. Verma, D. Miles, L. Gianni, I.E. Krop, M. Welslau, J. Baselga, M. Pegram, D. Y. Oh, V. Dieras, E. Guardino, et al., Trastuzumab emtansine for HER2-positive advanced breast cancer, N. Engl. J. Med. 367 (19) (2012) 1783–1791. K.D. Miller, V. Dieras, N. Harbeck, F. Andre, R.L. Mahtani, L. Gianni, K.S. Albain, D. Crivellari, L. Fang, G. Michelson, et al., Phase IIa trial of trastuzumab emtansine with pertuzumab for patients with human epidermal growth factor receptor 2-positive, locally advanced, or metastatic breast cancer, J. Clin. Oncol. 32 (14) (2014) 1437–1444. S.H. Giordano, S. Temin, J.J. Kirshner, S. Chandarlapaty, J.R. Crews, N. E. Davidson, F.J. Esteva, A.M. Gonzalez-Angulo, I. Krop, J. Levinson, et al., Systemic therapy for patients with advanced human epidermal growth factor receptor 2-positive breast cancer: American Society of Clinical Oncology clinical practice guideline, J. Clin. Oncol. 32 (19) (2014) 2078–2099. V. Dieras, N. Harbeck, G.T. Budd, J.K. Greenson, A.E. Guardino, M. Samant,
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N. Chernyukhin, M.C. Smitt, I.E. Krop, Trastuzumab emtansine in human epidermal growth factor receptor 2-positive metastatic breast cancer: an integrated safety analysis, J. Clin. Oncol. 32 (25) (2014) 2750–2757. J. Force, R. Saxena, B.P. Schneider, A.M. Storniolo, G.W. Sledge Jr., N. Chalasani, R. Vuppalanchi, Nodular regenerative hyperplasia after treatment with trastuzumab emtansine, J. Clin. Oncol. (2014), PMID: 24778392 [Epub ahead of print]. S. Chitturi, G.C. Farrell, Etiopathogenesis of nonalcoholic steatohepatitis, Semin. Liver Dis. 21 (1) (2001) 27–41. G.C. Farrell, C.Z. Larter, Nonalcoholic fatty liver disease: from steatosis to cirrhosis, Hepatology 43 (2006) S99–S112 2 Suppl 1. P.E. Steiner, Nodular regenerative hyperplasia of the liver, Am. J. Pathol. 35 (5) (1959) 943. S. Srinivasan, V. Parsa, C.Y. Liu, J.A. Fontana, Trastuzumab-induced hepatotoxicity, Ann. Pharmacother. 42 (10) (2008) 1497–1501. K. Ishizuna, J. Ninomiya, T. Ogawa, E. Tsuji, Hepatotoxicity induced by trastuzumab used for breast cancer adjuvant therapy: a case report, J. Med. Case Rep. 8 (2014) 417. X. Sun, W. Widdison, M. Mayo, S. Wilhelm, B. Leece, R. Chari, R. Singh, H. Erickson, Design of antibody-maytansinoid conjugates allows for efficient detoxification via liver metabolism, Bioconjugate Chem. 22 (4) (2011) 728–735. H.K. Erickson, J.M. Lambert, ADME of antibody-maytansinoid conjugates, AAPS J. 14 (4) (2012) 799–805. B.Q. Shen, D. Bumbaca, Q. Yue, O. Saad, J. Tibbitts, S.C. Khojasteh, S. Girish, Non-clinical disposition and metabolism of DM1, a Component of Trastuzumab Emtansine (T-DM1), in Sprague Dawley Rats, Drug Metab. Lett. 9 (2) (2015) 119–131. A.W. Tolcher, Cantuzumab Mertansine, a Maytansinoid Immunoconjugate Directed to the CanAg Antigen: a Phase I, Pharmacokinetic, and Biologic Correlative Study, J. Clin. Oncol. 21 (2) (2003) 211–222. H. Uppal, E. Doudement, K. Mahapatra, W.C. Darbonne, D. Bumbaca, B.Q. Shen, X. Du, O. Saad, K. Bowles, S. Olsen, et al., Potential mechanisms for thrombocytopenia development with trastuzumab emtansine (T-DM1), Clin. Cancer Res. 21 (1) (2015) 123–133.
Contents lists available at ScienceDirect
Cancer Treatment Communications journal homepage: www.elsevier.com/locate/ctrc
Trastuzumab emtansine associated nodular regenerative hyperplasia: A case report and review of literature L.H. Prochaska, I. Damjanov, R.M. Ash, J.C. Olson, Q.J. Khan, P. Sharma n University of Kansas Medical Center, 2330 Shawnee Mission Parkway, Westwood, KS, USA
art ic l e i nf o
a b s t r a c t
Article history: Received 30 July 2015 Received in revised form 17 November 2015 Accepted 29 November 2015
Background: Trastuzumab emtansine (T-DM1), a novel drug-antibody conjugate, has shown promising activity in HER2-positive breast cancer and is the recommended agent of choice for second line therapy for advanced HER 2-positive breast cancer. Elevations in transaminase levels have been reported in up to 40% of patients treated with T-DM1 on phase I-III clinical studies. More serious hepatotoxicity can also result from this drug-antibody conjugate, but has been infrequently described in the literature. Case Presentation: Here we report a 73 year old female with previously untreated metastatic HER 2-positive breast cancer who developed nodular regenerative hyperplasia and noncirrhotic portal hypertension while on treatment with single agent T-DM1. Liver biopsy demonstrated nodular regenerative hyperplasia, bile duct injury, and portal fibrosis. Conclusion: A high index of suspicion for liver injury and NRH must be maintained for patients who develop liver test abnormalities and/or signs of portal hypertension during treatment with T-DM1. Abdominal imaging, liver biopsy, and prompt discontinuation of T-DM1 is recommended for patients with signs or symptoms of liver injury. & 2015 Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Keywords: Trastuzumab emtanisine Metastatic HER2-positive breast cancer Nodular regenerative hyperplasia Noncirrhotic portal hypertension
1. Background Trastuzumab emtansine (T-DM1) is a drug-antibody conjugate linking trastuzumab to emtansine by non-reducible thioester linker, 4-[N-maleimidomethyl] cyclohexane-1 carboxylate (MCC) [1]. Trastuzumab is a monoclonal antibody targeting the human epidermal growth factor receptor-2 (HER2) and emtansine (DM-1), a maytansine derivative, and is a cytotoxic agent that acts by microtubule inhibition. The drug-antibody conjugate binds the HER2 receptor and becomes internalized whereby DM-1 can then disrupt the microtubules and cause cell death and apoptosis [2]. T-DM1 was first studied in patients with advanced HER 2-positive breast cancer in 2010 in a phase I trial, where substantial clinical benefit was noted [3]. The most common adverse events related to T-DM1 that were noted in the phase I study were thrombocytopenia (54.2%) and elevated transaminases (41.7%). Abbreviations: T-DM1, Trastuzumab emtansine; MCC, 4-[N-maleimidomethyl] cyclohexane-1 carboxylate; HER2, human epidermal growth receptor-2; DM-1, emtansine; NRH, nodular regenerative hyperplasia; ER, estrogen receptor; PR, progesterone recepton; TCH, docetaxel, carboplatin, Herceptin chemotherapy regimen; NCPH, noncirrhotic portal hypertension n Corresponding author. E-mail address: [email protected] (P. Sharma).
Subsequent phase II and III trials continued to show promising activity of T-DM1 in patients with heavily pretreated HER 2-positive advanced breast cancer leading to FDA approval of T-DM1 in the second line setting for treatment of advanced HER-2 positive metastatic breast cancer [4–8]. Transaminase elevation has been a known and common side effect associated with T-DM1, with mild grade 1–2 abnormalities noted in 31.8% and grade Z3 abnormalities noted in 7.4% in an integrated safety analysis [9]. Serious hepatotoxicity, including portal hypertension [3], cirrhosis [7], and rare cases of nodular regenerative hyperplasia (NRH) [9,10] have been recently reported in patients treated with T-DM1 on clinical trials. Most of these prior reports of portal hypertension and NRH associated with T-DM1 occurred in patients that were heavily pretreated with chemotherapy and HER 2 targeted therapy. The heavy amount of chemotherapy pretreatment may have primed these particular individuals for further injury with the maytansinoid portion of T-DM1. There have been no reported cases of NRH with T-DM1 when used as a first line therapy in metastatic breast cancer patients outside of clinical trials. Here we report a patient with previously untreated metastatic HER 2-positive breast cancer who developed NRH resulting in noncirrhotic portal hypertension and biliary duct injury while on treatment with single agent T-DM1.
http://dx.doi.org/10.1016/j.ctrc.2015.11.008 2213-0896/& 2015 Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
L.H. Prochaska et al. / Cancer Treatment Communications 5 (2016) 26–30
2. Case presentation
T-DM1 discontinued
2 1.5
AST ALT
1
Alk phos Bili
0.5 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 Months post T-DM1 initiation
250 230 210 T-DM1 discontinued
190 K/UL
A 73-year-old female was diagnosed with locally advanced estrogen receptor (ER) positive, progesterone receptor (PR) negative, HER 2-positive (HER 2 FISH 4.2), stage IIIA (T3N2) left breast CA in January 2010. She received 6 cycles of neoadjuvant Docetaxel, Carboplatin, Herceptin (TCH) and underwent modified radical mastectomy. Following surgery, she completed 52 weeks of adjuvant Herceptin and was placed on adjuvant endocrine therapy with anastrazole. She was found to have new mediastinal and right supraclavicular adenopathy in March 2013 and biopsy of the supraclavicular lymph node confirmed HER-2 positive, ER/PR negative metastatic breast cancer. T-DM1 3.6 mg/kg was initiated in April 2013 for treatment of her newly diagnosed metastatic disease. This was chosen as first line therapy due to patient’s age and her desire to avoid toxicities of conventional chemotherapy. CT scan of the abdomen prior to starting T-DM1 showed hepatic steatosis with otherwise normal liver and no evidence of portal hypertension. CT imaging in June 2013 showed improvement in the mediastinal lymphadenopathy and mild fatty liver that was unchanged (Fig. 1). Over the next 12 months she continued on T-DM1 with good control of the mediastinal metastatic disease. Liver function tests (AST/ALT/Alkaline phosphatase) fluctuated during this time period but stayed o2.5X ULN (Fig. 2A). Grade 1 thrombocytopenia was also noted after starting TDM-1 with a nadir of 99,000 while on therapy (Fig. 2B). CT abdomen in June 2014 (15 months after starting T-DM1) showed morphologic evidence of chronic liver disease with nodularity and slight widening of the fissure for the ligamentum teres hepatis, along with splenomegaly and esophageal varices (Fig. 1). At that time, T-DM1 was discontinued and liver workup was pursued. Hepatitis panel, anti-mitochondrial antibodies, ANA, and alpha-1 antitrypsin were all negative. Anti smooth muscle antibody titer was minimally elevated at 20 (reference range o20). Liver biopsy was performed in September 2014. Pathology demonstrated nodule-like expansion of the liver cell cords compressing the peripheral hepatocytes, consistent with nodular regenerative hyperplasia (Fig. 3A). Reticulin stain (Fig. 3B) demonstrated compressed hepatocytes, further supporting the diagnosis of NRH. Changes consistent with biliary duct injury were also noted. The CK7 immunohistochemistry showed bile duct loss from the portal tracts with a “blush staining of hepatocytes”, indicative of biliary metaplasia (Fig. 3). Abdominal CT from November 2014 continued to show persistent liver disease and evidence of portal hypertension. Esophagogastroduodenoscopy performed in February 2015 due to the portal hypertension showed esophageal varices, requiring banding. Clinical or radiological ascites was not noted and the patient did not demonstrate any symptoms associated with portal hypertension. Laboratory studies after T-DM1 discontinuation
X upper limits of normal (ULN)
2.5
27
170 150
platelets
130 110 90 70 50 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 Months post T-DM1 initiation
Fig. 2. Liver function tests (A) and platelet levels (B) in relation to T-DM1 initiation and discontinuation.
demonstrated normalization of AST and ALT at 6 months (Fig. 2A). Alkaline phosphatase also improved and was less than 1.5X ULN at 9-month follow up. Platelets improved but had not normalized by 9-month follow up (Fig. 2B). Fig. 4 outlines the treatment history leading to development of NRH. Patient remains off all anticancer therapy and without evidence of active breast cancer at this time.
3. Discussion T-DM1 is a drug-antibody conjugate consisting of trastuzumab, emtansine, and a thioester linker that has shown very promising activity in advanced HER 2-positive breast cancer. T-DM1 is an appealing treatment option for metastatic HER 2-positive breast cancer as it is devoid of toxicities associated with conventional cytotoxic agents. Transaminase elevations and thrombocytopenia with T-DM1 are well known with grade 3 and 4 events in acceptable ranges for treatment of advanced breast cancer. Mild transaminase elevation are noted in 30-40% of patients on TDM-1 and do not require interruption in therapy. However, patients with durable responses who remain on T-DM1 for long periods may develop more serious
Fig. 1. CT imaging changes following T-DM1 initiation.
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L.H. Prochaska et al. / Cancer Treatment Communications 5 (2016) 26–30
liver damage that goes unrecognized in the setting of persistent but mild LFT elevation. Nodular regenerative hyperplasia is a rare but serious complication of T-DM1 that has been reported in the literature, but never outside of a clinical trial. One case reported two patients on T-DM1 who developed noncirrhotic portal hypertension related to nodular regenerative hyperplasia [10] (Table 1). Both of these patients were on clinical trials, received TDM1 with other investigational agents, and had extensive prior treatment for metastatic disease. In an integrated toxicity analysis of six T-DM1 clinical trials, NRH was noted in 3 out of 884 patients (0.3%). All 3 patients developed portal hypertension and 1 patient died as a result of liver failure [9]. Our case reports a patient with previously untreated metastatic HER 2-positive breast cancer who developed NRH and asymptomatic noncirrhotic portal hypertension (NCPH) while on treatment with single agent T-DM1. To our knowledge, this is the first reported case of T-DM1 associated NRH in a non-clinical trial patient who received TDM-1 as first line treatment for metastatic HER 2-positive breast cancer. The risk of TDM-1 associated liver injury may be increased in patients with extensive prior treatment, but our case demonstrates that this risk is present even in patients who have not had any prior therapy for treatment of metastatic disease. The time from initiation of TDM-1 and NRH diagnosis in the above five patients ranged from 2 to 27 months and was greater than 12 months in 4 of the 5 previously reported cases. Our patient was diagnosed with NRH within a similar time frame, 15 months after initiation of T-DM1. Thus, chronicity of TDM-1 use seems to emerge as a potential risk factor for development of NRH. Age does not appear to relate given our relatively older patient (73 years) compared with younger patients (66 years and 50 years old) in one of the aforementioned trials [10]. Biological mechanisms that explain the link between chronicity of TDM-1 use and NRH are not clear and should be investigated further. It is possible that pre-existing fatty infiltration of liver increases the risk of NRH. Only two (of 5) previously reported cases of NRH provide information on the status of baseline liver function; one of which had hepatic steatosis prior to T-DM1 initiation. Interestingly, our patient also had CT evidence of mild fatty liver at baseline. It is known that fatty infiltration makes the liver more vulnerable to hepatocellular injury initiated by reactive oxygen species, which can be induced by drugs [11,12]. A direct correlation between hepatic steatosis and NRH has not been documented in the literature. NRH is characterized by hepatic parenchyma transformation into nodules with innumerable areas of focal regeneration demarcated by adjacent compressive, atrophic, degenerative, and circulatory effects [13]. This damage leads to NCPH, as seen in our patient and those in the literature. The intralobular fibrosis in response to the liver cell injury and loss of injured hepatocytes can
Fig. 3. Nodular regenerative hyperplasia (A) Hepatocytes form indistinct small nodules (arrows) compressing the surrounding cells. H&E 160. (B) Reticulin stain outlines the nodules and the compressed hepatocytes around them ( 160). (C) Immunohistochemical stain with antibodies to cytokeratin that stains selectively the bile ducts and ductules. The lower lobule shows a ductal reaction around a portal tract missing the primary duct (bottom part of the figure). In the upper lobule there is a “blush-like” staining of periportal hepatocytes undergoing ductal metaplasia ( 220). (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)
T-DM 1initiated
1/2010
6 cycles TCH
Diagnosed with stage III breast cancer ER+, HER2+
T-DM1 discontinued
Adjuvant Herceptin completed
8/2010
Adjuvant Anastrazole initiated
Modified radical mastectomy
3/2013
Diagnosed with metastatic breast cancer ER-, HER2+
4/2013
6/2014
9/2014
CT showed liver disease and portal hypertension
NRH diagnosed via liver biopsy
Fig. 4. Treatment history timeline leading to development of NRH.
L.H. Prochaska et al. / Cancer Treatment Communications 5 (2016) 26–30
29
Table 1 Summary of previously reported cases of NRH. Age
Line of therapy
Previous Treatment regimensa
Concomitant drugsb
Start of T-DM1 until NRH diagnosis
Time to LFT recovery
73c 55
First Eighth
None Pertuzumab
15 months 15 months
6 months 1 month
39
Fourth
No previous therapy in metastatic setting Doxorubicin þ carboplatinþ paclitaxel Taxotereþtrastuzumab Navelbineþ trastuzumab Capecitabine þvincristine þfluorouracil þ bevacizumab þ trastuzumab Oxaliplatin þ fluorouracil þbevacizumab þtrastuzumab Gemcitabine þ lapatinib Paclitaxelþ trastuzumabþalvespimycin Paclitaxelþ carboplatin þtrastuzumab Paclitaxelþ carboplatin þlapatinib Navelbineþ traztuzumab Unk Unk Unk
Pictilisib (GDC-0941)
17 months
2 months
3 months 27 months 15 months
Unk Unk Unk
Unk Unk Unk Unk Unk Unk a b c
In metastatic setting. Administered along with with T-DM1, LFT ¼ Liver Function tests, Unk ¼unknown. Current cases.
explain the AST and ALT elevations. One thing that could not be explained by NRH in our patient was the bile duct injury confirmed on liver biopsy. The bile ductular injury explains elevation in alkaline phosphatase and bilirubin noted in our patient, which were rarely elevated in the abovementioned reports. Given no obvious bile duct obstruction and the temporal association of alkaline phosphatase elevation and T-DM1 initiation/discontinuation in our patient, it is suspected that T-DM1 also contributed to this pathology. Despite the noted incidence of hepatic injury in patients treated with T-DM-1, the mechanism in which this occurs is still not clear. Internalization of T-DM1 into Fc-receptor-bearing Kupffer cells with subsequent release of free DM1 into the local microenvironment is one potential explanation. T-DM1 related hepatic injury due to low levels of free DM1 briefly observed in the systemic circulation after T-DM1 is another possibility [3]. Trastuzumab alone has only rarely been reported to cause elevated transaminases and there are no reports of single agent trastuzumab related NRH [14,15]. Trastuzumab in combination with chemotherapy has led to elevated transaminases (grade r2) in clinical trials, but it difficult to know if hepatotoxicity in this setting was chemotherapy or monoclonal antibody related [5]. Similarly, emtansine alone has not been documented to cause NRH, however it is well described that the liver plays an important role in degradation and detoxification of antibody-maytansinoid conjugates [16–18]. It is possible that hepatic injury may be more of a class effect since elevation in transaminase levels are not limited to the trastuzumab emtansine conjugate but have also been seen with other drug-antibody conjugates [19]. The mechanisms by which thrombocytopenia results from T-DM1 have been studied in the literature and is felt in large to be related to T-DM1-induced impairment of megakaryocyte differentiation [20], but liver damage leading to portal hypertension and splenic sequestration may also be playing a role in some patients. In conclusion, a high index of suspicion for drug-induced NRH must be maintained in patients undergoing treatment with TDM-1 and elevations in transaminase levels should be monitored closely. The frequent transaminase elevations noted in patients on treatment with T-DM1 may lead to under-investigation of other etiologies of the liver function test abnormalities, as was the case for our patient. Our patient was asymptomatic and further investigation including liver biopsy was undertaken only after radiologic evidence of portal hypertension was noted. We suggest that patients who continue on T-DM1 treatment for greater than 12 months and have grade 1 or 2 transaminitis should undergo a
regular evaluation for portal hypertension and NRH with appropriate imaging. Future research efforts should focus on early detection of NRH (prior to development of portal hypertension) and identifying risk factors associated with development of this liver injury.
4. Consent Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.
Competing interests The authors declare that they have no competing financial interests.
Authors' contributions LHP, ID, RMA, JCO, QJK, PS obtained the data LHP, ID, RMA, JCO, QJK, PS documented the case and LHP, ID, RMA, JCO, QJK, PS performed the literature search LHP, ID, RMA, JCO, QJK, PS contributed to the writing process LHP, ID, RMA, JCO, QJK, PS critically reviewed the data LHP, ID, RMA, JCO, QJK, PS contributed to the writing process All authors read and approved the final manuscript.
Acknowledgments None.
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