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Telangiectasia and Pulmonary Arterial Hypertension Following Treatment With Trastuzumab Emtansine
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Selected Reports
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Telangiectasia and Pulmonary Arterial Hypertension Following Treatment With Trastuzumab Emtansine A Case Report Younghoon Kwon, MD; Mardi Gomberg-Maitland, MD; Marc Pritzker, MD; and Thenappan Thenappan, MD
Trastuzumab emtansine (T-DM1) is a Food and Drug Administration–approved novel agent for the treatment of HER-2 positive advanced breast cancer. We report a case of pulmonary arterial hypertension (PAH) that we attribute to the use of T-DM1. A 43-year-old woman with stage IV breast cancer presented with dyspnea on exertion. After excluding other secondary causes of pulmonary hypertension, a diagnosis of moderately severe PAH was made based on right heart catheterization. History revealed that the patient had been on T-DM1 before presentation. During T-DM1 treatment, the patient experienced hereditary hemorrhagic telangiectasia–like symptoms consisting of spider angiomata-skin lesions, epistaxis, and hematochezia, which resolved with discontinuation of T-DM1. Temporal associations of T-DM1 use with the development of PAH in the patient, and the reported association between hereditary hemorrhagic telangiectasia and PAH via genetic linkage, led us to suspect T-DM1 as the cause of PAH. CHEST 2016; 149(4):e103–e105 KEY WORDS:
chemotherapy; oncology; pulmonary hypertension
Trastuzumab emtansine (T-DM1) is a novel agent that has emerged as a new standard of care for HER2-positive breast cancer that progresses despite multiple lines of HER2-directed therapy.1 We report a case of pulmonary arterial hypertension (PAH) that we attribute to the use of T-DM1.
Case Report A 43-year-old woman was referred to the cardiology clinic because of several months of worsening dyspnea on exertion. Her history
ABBREVIATIONS:
PAH = pulmonary arterial hypertension; T-DM1 = trastuzumab emtansine AFFILIATIONS: From the Division of Cardiovascular Medicine, Department of Medicine (Drs Kwon, Pritzker, and Thenappan), University of Minnesota, Minneapolis, MN; and Division of Cardiovascular Medicine, Department of Medicine (Dr Gomberg-Maitland), University of Chicago, Chicago, IL. FUNDING/SUPPORT: Dr Thenappan is funded by the American Heart Association Scientist Development Grant 15SDG25560048.
journal.publications.chestnet.org
was remarkable for stage IV breast cancer (HER-2 positive) diagnosed 6 years before the visit, for which she had undergone a series of chemotherapy in conjunction with surgical resection and radiation therapy. She received neoadjuvant 5-fluorouracil, epirubicin, cyclophosphamide; paclitaxel; and trastuzumab followed by lumpectomy and axillary dissection. Three years before this presentation, the patient was enrolled in a clinical trial for metastatic breast cancer and received T-DM1 in addition to either
CORRESPONDENCE TO: Thenappan Thenappan, MD, Section of Advanced Heart Failure and Pulmonary Hypertension, Cardiovascular Division, University of Minnesota Medical School, 420 Delaware Street SE, MMC 508, Minneapolis, MN 55455; e-mail: [email protected] Copyright Ó 2016 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved. DOI: http://dx.doi.org/10.1016/j.chest.2015.09.008
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pertuzumab or placebo. After six cycles of T-DM1 pertuzumab, she developed an acne-like, spider angiomata-appearing rash all over her body (Fig 1) along with increased bruising, gingival bleeding, epistaxis from nasal mucosal bleeding, and hematochezia from rectal mucosal bleeding. Biopsy of her skin lesion was consistent with telangiectasia (Fig 2). Colonoscopy showed no other obvious source of bleeding. In addition, she noticed exertional shortness of breath and fatigue. The patient continued to have waxing and waning symptoms for 2 years until she decided to exit the trial after 31 cycles, with significant improvement in her telangiectasia. However, she continued to have progressive worsening of dyspnea on exertion. History and physical examination were otherwise unremarkable. Transthoracic echocardiography revealed normal left ventricular function, but moderate dilatation of the right ventricle with flattening of the interventricular septum, suggestive of pulmonary hypertension. Agitated saline contrast study excluded intracardiac and intrapulmonary shunt. Chest CT and ventilation perfusion scans ruled out pulmonary embolism. A pulmonary function test was unremarkable. Subsequent right heart catheterization confirmed moderately severe pulmonary hypertension (mean right atrial pressure, 6 mm Hg; pulmonary artery pressure, 58/23 (36) mm Hg; mean pulmonary capillary wedge pressure, 6 mm Hg; cardiac output, 3.6 liter/min; and pulmonary vascular resistance 7.1 Wood units). The patient had no acute vasodilator response with inhaled nitric oxide. Coronary angiogram was unremarkable. Her serological workup for other associated causes of PAH was negative. A diagnosis of PAH was made and she was subsequently started on a phosphodiesterase-5 inhibitor. The patient responded well, with significant
Figure 1 – Acne-like spider angiomata-appearing rash on the patient’s chest while she was on trastuzumab emtansine therapy.
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Figure 2 – Pathology of biopsy specimen from acne-like spider angiomata lesion (original magnification 20).
improvement in exercise capacity and normalization of right ventricular function by echocardiography.
Discussion Although PAH in the patient can be coincidental, the temporal relationship between the exposure to T-DM1 and the clinical manifestation of PAH suggests that it is likely related to T-DM1. Pulmonary hypertension has been previously reported in a phase I study of T-DM1.2 Furthermore, the mucocutaneous telangiectasia observed in the patient with T-DM1 therapy mimics the classic presentation of hereditary hemorrhagic telangiectasia (HHT), which has been associated with PAH via genetic linkage. The presence of solid-organ arteriovenous malformation, another important hallmark of HHT, though not confirmed, was also suggested by episodes of hematochezia without any other clear source of gastrointestinal bleeding. Extensive mucocutaneous telangiectasia similar to that described in our case has been reported in relation to T-DM1 treatment.3 Although the exact mechanism is unclear, disruption of cytoskeletal microtubules and apoptosis of potentially HER2-expressing endothelial cells4 by the emtansine component of T-DM1 may explain mucocutaneous telangiectasia and distal small vessel vasculopathy leading to PAH. Indeed, T-DM1 causing an HHT-like manifestation may be an important clue to the underlying cause of PAH in the patient. Mutations in genes that code for components of the transforming growth factor-b receptor, such as activin receptor-like kinase 1 (ALK-1) and endoglin, have been reported in PAH associated with HHT.5 Mutations in ALK-1 in particular have been associated with proliferative
[
149#4 CHEST APRIL 2016
]
plexiform vasculopathy of the small pulmonary arteries that is characteristic of PAH.6 Thus, although genetic analysis was not performed in the patient, we postulate that alteration in ALK-1 may have been involved in the underlying pathogenesis of telangiectasia and PAH with T-DM1 therapy. Normal cardiac output and elevated pulmonary vascular resistance exclude the possibility of systemic atrioventricular shunting as a potential cause of pulmonary hypertension in the patient. Hematogenous spread of breast cancer to the pulmonary vasculature can lead to pulmonary hypertension. We did not perform pulmonary microvasculature cytology7; nonetheless, the presence of low-probability ventilation perfusion scan, unremarkable chest CT scan, and good response to PAH-specific vasodilator therapy makes tumor embolism less likely in this patient. Finally, although the patient’s rash can be attributed to pertuzumab, which the patient may have received during the trial, there are no prior reports linking pertuzumab to HHT-mimicking reaction or PAH.
Acknowledgments
Conclusions
5. Harrison RE, Flanagan JA, Sankelo M, et al. Molecular and functional analysis identifies ALK-1 as the predominant cause of pulmonary hypertension related to hereditary haemorrhagic telangiectasia. J Med Genet. 2003;40(12):865-871.
We report a case of HHT-like manifestation with mucocutaneous telangiectasia and PAH in association with TDM-1 treatment. Given the adverse outcome associated with PAH and the prospect of increasing use of TDM-1 for patients with metastatic breast cancer, we propose a careful assessment of any PAH incidence among those receiving this drug.
journal.publications.chestnet.org
Author contributions: Y. K., M. P., and T. T. conceived the article. Y. K., M. G.-M., M. P., and T. T. drafted the manuscript for important intellectual content. Financial/Nonfinancial disclosures: None declared. Role of sponsors: The sponsor had no role in the design of the study, the collection and analysis of the data, or the preparation of the manuscript. Other contributions: The authors thank Justin Peltola, MD (Department of Pathology, University of Minnesota), for his assistance with the pathology slide and Ms Roberta Beach, BS, for editing the manuscript. CHEST worked with the authors to ensure that the Journal policies on patient consent to report information were met.
References 1. Verma S, Miles D, Gianni L, et al. Trastuzumab emtansine for HER2positive advanced breast cancer. N Engl J Med. 2012;367(19):1783-1791. 2. 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 HER2-positive metastatic breast cancer. J Clin Oncol. 2010; 28(16):2698-2704. 3. Sibaud V, Niec RE, Schindler K, et al. Ado-trastuzumab emtansineassociated telangiectasias in metastatic breast cancer: a case series. Breast Cancer Res Treat. 2014;146(2):451-456. 4. Krahn G, Leiter U, Kaskel P, et al. Coexpression patterns of EGFR, HER2, HER3 and HER4 in non-melanoma skin cancer. Eur J Cancer. 2001;37(2):251-259.
6. Trembath RC, Thomson JR, Machado RD, et al. Clinical and molecular genetic features of pulmonary hypertension in patients with hereditary hemorrhagic telangiectasia. N Engl J Med. 2001; 345(5):325-334. 7. Masson RG, Krikorian J, Lukl P, Evans GL, McGrath J. Pulmonary microvascular cytology in the diagnosis of lymphangitic carcinomatosis. N Engl J Med. 1989;321(2):71-76.
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Selected Reports
]
Telangiectasia and Pulmonary Arterial Hypertension Following Treatment With Trastuzumab Emtansine A Case Report Younghoon Kwon, MD; Mardi Gomberg-Maitland, MD; Marc Pritzker, MD; and Thenappan Thenappan, MD
Trastuzumab emtansine (T-DM1) is a Food and Drug Administration–approved novel agent for the treatment of HER-2 positive advanced breast cancer. We report a case of pulmonary arterial hypertension (PAH) that we attribute to the use of T-DM1. A 43-year-old woman with stage IV breast cancer presented with dyspnea on exertion. After excluding other secondary causes of pulmonary hypertension, a diagnosis of moderately severe PAH was made based on right heart catheterization. History revealed that the patient had been on T-DM1 before presentation. During T-DM1 treatment, the patient experienced hereditary hemorrhagic telangiectasia–like symptoms consisting of spider angiomata-skin lesions, epistaxis, and hematochezia, which resolved with discontinuation of T-DM1. Temporal associations of T-DM1 use with the development of PAH in the patient, and the reported association between hereditary hemorrhagic telangiectasia and PAH via genetic linkage, led us to suspect T-DM1 as the cause of PAH. CHEST 2016; 149(4):e103–e105 KEY WORDS:
chemotherapy; oncology; pulmonary hypertension
Trastuzumab emtansine (T-DM1) is a novel agent that has emerged as a new standard of care for HER2-positive breast cancer that progresses despite multiple lines of HER2-directed therapy.1 We report a case of pulmonary arterial hypertension (PAH) that we attribute to the use of T-DM1.
Case Report A 43-year-old woman was referred to the cardiology clinic because of several months of worsening dyspnea on exertion. Her history
ABBREVIATIONS:
PAH = pulmonary arterial hypertension; T-DM1 = trastuzumab emtansine AFFILIATIONS: From the Division of Cardiovascular Medicine, Department of Medicine (Drs Kwon, Pritzker, and Thenappan), University of Minnesota, Minneapolis, MN; and Division of Cardiovascular Medicine, Department of Medicine (Dr Gomberg-Maitland), University of Chicago, Chicago, IL. FUNDING/SUPPORT: Dr Thenappan is funded by the American Heart Association Scientist Development Grant 15SDG25560048.
journal.publications.chestnet.org
was remarkable for stage IV breast cancer (HER-2 positive) diagnosed 6 years before the visit, for which she had undergone a series of chemotherapy in conjunction with surgical resection and radiation therapy. She received neoadjuvant 5-fluorouracil, epirubicin, cyclophosphamide; paclitaxel; and trastuzumab followed by lumpectomy and axillary dissection. Three years before this presentation, the patient was enrolled in a clinical trial for metastatic breast cancer and received T-DM1 in addition to either
CORRESPONDENCE TO: Thenappan Thenappan, MD, Section of Advanced Heart Failure and Pulmonary Hypertension, Cardiovascular Division, University of Minnesota Medical School, 420 Delaware Street SE, MMC 508, Minneapolis, MN 55455; e-mail: [email protected] Copyright Ó 2016 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved. DOI: http://dx.doi.org/10.1016/j.chest.2015.09.008
e103
pertuzumab or placebo. After six cycles of T-DM1 pertuzumab, she developed an acne-like, spider angiomata-appearing rash all over her body (Fig 1) along with increased bruising, gingival bleeding, epistaxis from nasal mucosal bleeding, and hematochezia from rectal mucosal bleeding. Biopsy of her skin lesion was consistent with telangiectasia (Fig 2). Colonoscopy showed no other obvious source of bleeding. In addition, she noticed exertional shortness of breath and fatigue. The patient continued to have waxing and waning symptoms for 2 years until she decided to exit the trial after 31 cycles, with significant improvement in her telangiectasia. However, she continued to have progressive worsening of dyspnea on exertion. History and physical examination were otherwise unremarkable. Transthoracic echocardiography revealed normal left ventricular function, but moderate dilatation of the right ventricle with flattening of the interventricular septum, suggestive of pulmonary hypertension. Agitated saline contrast study excluded intracardiac and intrapulmonary shunt. Chest CT and ventilation perfusion scans ruled out pulmonary embolism. A pulmonary function test was unremarkable. Subsequent right heart catheterization confirmed moderately severe pulmonary hypertension (mean right atrial pressure, 6 mm Hg; pulmonary artery pressure, 58/23 (36) mm Hg; mean pulmonary capillary wedge pressure, 6 mm Hg; cardiac output, 3.6 liter/min; and pulmonary vascular resistance 7.1 Wood units). The patient had no acute vasodilator response with inhaled nitric oxide. Coronary angiogram was unremarkable. Her serological workup for other associated causes of PAH was negative. A diagnosis of PAH was made and she was subsequently started on a phosphodiesterase-5 inhibitor. The patient responded well, with significant
Figure 1 – Acne-like spider angiomata-appearing rash on the patient’s chest while she was on trastuzumab emtansine therapy.
e104 Selected Reports
Figure 2 – Pathology of biopsy specimen from acne-like spider angiomata lesion (original magnification 20).
improvement in exercise capacity and normalization of right ventricular function by echocardiography.
Discussion Although PAH in the patient can be coincidental, the temporal relationship between the exposure to T-DM1 and the clinical manifestation of PAH suggests that it is likely related to T-DM1. Pulmonary hypertension has been previously reported in a phase I study of T-DM1.2 Furthermore, the mucocutaneous telangiectasia observed in the patient with T-DM1 therapy mimics the classic presentation of hereditary hemorrhagic telangiectasia (HHT), which has been associated with PAH via genetic linkage. The presence of solid-organ arteriovenous malformation, another important hallmark of HHT, though not confirmed, was also suggested by episodes of hematochezia without any other clear source of gastrointestinal bleeding. Extensive mucocutaneous telangiectasia similar to that described in our case has been reported in relation to T-DM1 treatment.3 Although the exact mechanism is unclear, disruption of cytoskeletal microtubules and apoptosis of potentially HER2-expressing endothelial cells4 by the emtansine component of T-DM1 may explain mucocutaneous telangiectasia and distal small vessel vasculopathy leading to PAH. Indeed, T-DM1 causing an HHT-like manifestation may be an important clue to the underlying cause of PAH in the patient. Mutations in genes that code for components of the transforming growth factor-b receptor, such as activin receptor-like kinase 1 (ALK-1) and endoglin, have been reported in PAH associated with HHT.5 Mutations in ALK-1 in particular have been associated with proliferative
[
149#4 CHEST APRIL 2016
]
plexiform vasculopathy of the small pulmonary arteries that is characteristic of PAH.6 Thus, although genetic analysis was not performed in the patient, we postulate that alteration in ALK-1 may have been involved in the underlying pathogenesis of telangiectasia and PAH with T-DM1 therapy. Normal cardiac output and elevated pulmonary vascular resistance exclude the possibility of systemic atrioventricular shunting as a potential cause of pulmonary hypertension in the patient. Hematogenous spread of breast cancer to the pulmonary vasculature can lead to pulmonary hypertension. We did not perform pulmonary microvasculature cytology7; nonetheless, the presence of low-probability ventilation perfusion scan, unremarkable chest CT scan, and good response to PAH-specific vasodilator therapy makes tumor embolism less likely in this patient. Finally, although the patient’s rash can be attributed to pertuzumab, which the patient may have received during the trial, there are no prior reports linking pertuzumab to HHT-mimicking reaction or PAH.
Acknowledgments
Conclusions
5. Harrison RE, Flanagan JA, Sankelo M, et al. Molecular and functional analysis identifies ALK-1 as the predominant cause of pulmonary hypertension related to hereditary haemorrhagic telangiectasia. J Med Genet. 2003;40(12):865-871.
We report a case of HHT-like manifestation with mucocutaneous telangiectasia and PAH in association with TDM-1 treatment. Given the adverse outcome associated with PAH and the prospect of increasing use of TDM-1 for patients with metastatic breast cancer, we propose a careful assessment of any PAH incidence among those receiving this drug.
journal.publications.chestnet.org
Author contributions: Y. K., M. P., and T. T. conceived the article. Y. K., M. G.-M., M. P., and T. T. drafted the manuscript for important intellectual content. Financial/Nonfinancial disclosures: None declared. Role of sponsors: The sponsor had no role in the design of the study, the collection and analysis of the data, or the preparation of the manuscript. Other contributions: The authors thank Justin Peltola, MD (Department of Pathology, University of Minnesota), for his assistance with the pathology slide and Ms Roberta Beach, BS, for editing the manuscript. CHEST worked with the authors to ensure that the Journal policies on patient consent to report information were met.
References 1. Verma S, Miles D, Gianni L, et al. Trastuzumab emtansine for HER2positive advanced breast cancer. N Engl J Med. 2012;367(19):1783-1791. 2. 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 HER2-positive metastatic breast cancer. J Clin Oncol. 2010; 28(16):2698-2704. 3. Sibaud V, Niec RE, Schindler K, et al. Ado-trastuzumab emtansineassociated telangiectasias in metastatic breast cancer: a case series. Breast Cancer Res Treat. 2014;146(2):451-456. 4. Krahn G, Leiter U, Kaskel P, et al. Coexpression patterns of EGFR, HER2, HER3 and HER4 in non-melanoma skin cancer. Eur J Cancer. 2001;37(2):251-259.
6. Trembath RC, Thomson JR, Machado RD, et al. Clinical and molecular genetic features of pulmonary hypertension in patients with hereditary hemorrhagic telangiectasia. N Engl J Med. 2001; 345(5):325-334. 7. Masson RG, Krikorian J, Lukl P, Evans GL, McGrath J. Pulmonary microvascular cytology in the diagnosis of lymphangitic carcinomatosis. N Engl J Med. 1989;321(2):71-76.
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