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Trastuzumab and thyroid dysfunction: An association to be aware of

1 Department of Medical Oncology, University of Navarra Clinic, Pamplona, Spain
2 Service of Pharmacy, University of Navarra Clinic, Pamplona, Spain
3 Service of Biochemistry, University of Navarra Clinic, Pamplona, Spain

Date of Submission24-Jan-2019
Date of Decision22-May-2019
Date of Acceptance17-Oct-2019
Date of Web Publication09-Jun-2020

Correspondence Address:
Marta Santisteban Eslava,
Department of Medical Oncology, University of Navarra Clinic, Avenida Pío XII,36, CP 31008, Pamplona
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jcrt.JCRT_66_19

 > Abstract 

The incidence of autoimmune thyroid disorders is higher among women with breast cancer (BC) than in other solid malignancies, while it has not a prognostic impact. Trastuzumab (T) is a humanized monoclonal antibody approved for human epidermal growth factor receptor 2 (HER2)-positive BC in the neoadjuvant, adjuvant, and metastatic scenarios. Since 2014, subcutaneous (SC) T has been employed with the same efficacy as the intravenous formulation together with an easier way of administration. To date, autoimmune thyroiditis has been linked rarely to the use of intravenous T, and no cases have been related to the SC presentation. We report two cases of HER2-positive early BC patients who developed hypothyroidism during maintenance therapy with SC T that required levothyroxine supplementation. SC T includes recombinant human hyaluronidase to facilitate tissue penetration of the drug. This enzyme may alter the thyroid gland stroma and facilitate the development of thyroid disorders. Thyroid function tests are recommended in patients on SC T.

Keywords: Breast cancer, subcutaneous trastuzumab, thyroid dysfunction

How to cite this URL:
Sánchez-Bayona R, Garcia del Barrio MA, Alegre E, Fernandez-Hidalgo OA, Eslava MS. Trastuzumab and thyroid dysfunction: An association to be aware of. J Can Res Ther [Epub ahead of print] [cited 2022 Aug 7]. Available from: https://www.cancerjournal.net/preprintarticle.asp?id=286253

 > Introduction Top

The association between thyroid disorders and breast cancer (BC) has been widely studied, with controversial results.[1],[2] In the same way, higher titers of antibodies to thyroid peroxidase (TPO Ab) were found in women with BC as compared to women with colorectal cancer and healthy controls, respectively.[2],[3]

Nowadays, the use of monoclonal antibodies in medical oncology has increased, notably becoming a standard treatment for many tumors (i.e., BC, colo-rectal carcinoma, lung carcinoma, melanoma). Although anti-HER2 mabs have been rarely related to autoimmune thyroid disorders (AITD), check-point inhibitors (CPI) are associated with an increased incidence of them. Trastuzumab (T) is a monoclonal antibody that targets the extracellular domain of the human epidermal growth factor receptor 2 (HER2). T has been approved in clinical practice in HER2-positive early and metastatic BC.[3] Since 2014, T is available for subcutaneous (SC) administration in a fixed dosage providing an easier and more feasible application without added toxicities.[4] Secondary thyroid dysfunction, although rare, has been described with the use of intravenous T but never with the SC formulation. Among 11 women treated in our center with SC T as a maintenance therapy, two of them (18%) have developed or impaired an AITD. Here, we introduce these two cases.

 > Case Reports Top

Case 1

A 60-year-old female was diagnosed with a luminal B-HER2-enriched subtype Stage II BC in April 2016. The patient received neoadjuvant treatment based on chemotherapy plus T. On December 2016, she started maintenance treatment with anastrozole and SC T 600 mg every 3 weeks. After the eighth dose of SC T, she developed Grade 1 asthenia. Blood sample test revealed an increased thyroid-stimulating hormone (TSH) of 43 μU/ml (normal values: 0.4–4.7 μU/ml) and free T4 of 8.5 pmol/L (normal values: 9–24 pmol/L). Anti-thyroglobulin test was positive (2.3 U, normal range: ≤0.6 U) and anti-TPO Ab was negative (27 U WHO, normal range: ≤100 U WHO). Previous values of TSH and T4 were normal. The diagnosis of primary autoimmune hypothyroidism was made, and the patient was started treatment with levothyroxine 75 mcg p.o. daily.

Case 2

A 43-year-old female with a medical history of AITD was diagnosed in 2010 and was treated with levothyroxine. She was diagnosed with HER2, Stage I BC on August 2016. The patient underwent tumorectomy and after that, adjuvant chemotherapy plus T was administered. On April 2017, she started maintenance treatment with SC T at standard doses. Before the fifth maintenance dose of T, the blood test showed an elevated value of TSH (30 μU/mL) with free T4 of 11 pmol/L. The patient referred an increasing weakness and a mild weight gain. Due to an exacerbation of the autoimmune hypothyroidism, the daily dose of levothyroxine was increased.

 > Discussion Top

Autoimmune hypothyroidism is more prevalent among women with BC than in other solid tumors, but neither this scenario nor other thyroid dysfunction is considered prognostic factors in this population. Hypothyroidism is more common than hyperthyroidism, and the pathophysiology is thought to be mediated by the T-cells and not by the B-cells autoimmunity.[1]

Comparison of SC versus intravenous T in the neoadjuvant and adjuvant settings demonstrates the same safety with similar (noninferiority) efficacy in survival with both formulations. SC T has a fixed dosage even though it has been published that some anthropometric measures, such as the body mass index (BMI), may influence the plasma concentrations of T.[5] Although the BMI does not determine the fixed dose of SC T, BMI over 30 kg/m[2] is associated with infratherapeutic plasma concentrations in 52% of gastric cancer patients. We could hypothesize that a lower BMI could be related to increase responses and toxicity (BMI of 25 and 22.4 kg/m[2], respectively, in our patients). Besides, we have ruled out an interference reaction among T and thyroid hormones in vitro.

To date, AITD has been found in up to 0.3% of cases related to the use of intravenous T.[6] The product information from the European Medicines Agency describes endocrine adverse events in 1.3% of the patients in both intravenous and SC administration of T, respectively, and AITD is only detected in the intravenous arm in 0.3% of the patients.[7] However, a higher rate of antidrug antibodies against T was seen with the SC formulation that is not related to adverse events. To our best knowledge, these are the first published cases of AITD related to SC T.

Recombinant human hyaluronidase (rHuPH20) is an essential component of SC formulations with a half-life of 15–20 h that acts as a permeation enhancer. Hyaluronidase is an enzyme that hydrolyzes and degrades the hyaluronan to facilitate the injection and absorption of drugs administered subcutaneously. Hyaluronan is a megadalton glycosaminoglycan that constitutes the extracellular matrix together with collagen. The levels of hyaluronan derived from thyrocytes and stromal fibroblasts are also increased in thyroid tissue from individuals with both Grave's disease and Hashimoto's thyroiditis compared with normal glands.[8]

One possible explanation to link SC T and thyroid disorders is that hyaluronan is degraded by rHuPH20, and it may facilitate the accumulation of T-cells in the thyroid gland and other target organs, as described in preclinical models of colorectal cancer,[9] triggering T-cell-mediated AITD. Moreover, treatment-induced antibodies against the rHuPH20 were described in 2%–18% of the cases, although they were related to no adverse events with the coadministered SC drugs.

Immune disorders related to monoclonal antibodies in patients with preexisting autoimmune diseases have been described in up to 75% of the patients. In 40% of the cases, it is due to an exacerbation of a previous immune disorder, and 25% can be considered de novo cases (related to the appearance of new immune disorders). In the remaining 10%, there is a combination of both new and de novo cases.[10] In our cohort of 11 patients treated with SC T, one patient developed de novo hypothyroidism and another patient had an exacerbation of a previous AITD.

In conclusion, there could be an association between SC T and AITD in HER2 BC patients. This phenomenon may be due to an increased T-cell recruitment driven by the rHuPH20 used in the SC formulation. Our recommendation is to perform thyroid function tests before and during SC T. Long-lasting supplements with levothyroxine are enough and adequate to reverse immune-related hypothyroidism.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

 > References Top

Grani G, Dicorato P, Dainelli M, Coletta I, Calvanese A, Del Sordo M, et al. Thyroid diseases in women with breast cancer. Clin Ter 2012;163:e401-4.  Back to cited text no. 1
Jiskra J, Barkmanova J, Limanova Z, Lánská V, Smutek D, Potlukova E, et al. Thyroid autoimmunity occurs more frequently in women with breast cancer compared to women with colorectal cancer and controls but it has no impact on relapse-free and overall survival. Oncol Rep 2007;18:1603-11.  Back to cited text no. 2
Cardoso F, Senkus E, Costa A, Papadopoulos E, Aapro M, André F, et al. 4th ESO-ESMO international consensus guidelines for advanced breast cancer (ABC 4)†. Ann Oncol 2018;29:1634-57.  Back to cited text no. 3
Ismael G, Hegg R, Muehlbauer S, Heinzmann D, Lum B, Kim SB, et al. Subcutaneous versus intravenous administration of (neo) adjuvant trastuzumab in patients with HER2-positive, clinical stage I-III breast cancer (HannaH study): A phase 3, open-label, multicentre, randomised trial. Lancet Oncol 2012;13:869-78.  Back to cited text no. 4
González García J, Gutiérrez Nicolás F, Nazco Casariego GJ, Batista López JN, Ceballos Lenza I, Ramos Díaz R, et al. Influence of anthropometric characteristics in patients with her2-positive breast cancer on initial plasma concentrations of trastuzumab. Ann Pharmacother 2017;51:976-80.  Back to cited text no. 5
Guaraldi F, La Selva R, Samà MT, D'Angelo V, Gori D, Fava P, et al. Characterization and implications of thyroid dysfunction induced by immune checkpoint inhibitors in real-life clinical practice: A long-term prospective study from a referral institution. J Endocrinol Invest 2018;41:549-56.  Back to cited text no. 6
European Medicines Agency. Committee for Medicinal Products for Human Use (CHMP) Assessment Report: Herceptin. European Medicines Agency; 2013.  Back to cited text no. 7
Rosengren S, Dychter SS, Printz MA, Huang L, Schiff RI, Schwarz HP, et al. Clinical immunogenicity of rHuPH20, a hyaluronidase enabling subcutaneous drug administration. AAPS J 2015;17:1144-56.  Back to cited text no. 8
Alaniz L, Rizzo M, Malvicini M, Jaunarena J, Avella D, Atorrasagasti C, et al. Low molecular weight hyaluronan inhibits colorectal carcinoma growth by decreasing tumor cell proliferation and stimulating immune response. Cancer Lett 2009;278:9-16.  Back to cited text no. 9
Abdel-Wahab N, Shah M, Lopez-Olivo MA, Suarez-Almazor ME. Use of immune checkpoint inhibitors in the treatment of patients with cancer and preexisting autoimmune disease: A Systematic review. Ann Intern Med 2018;168:121-30.  Back to cited text no. 10


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