Can hypothyroidism, as evidenced by a Thyroid-Stimulating Hormone (TSH) level of less than 0.1, be related to treatment with Cobimetinib (Cotellic) and Vemurafenib (Zelboraf) in a 30-year-old male patient with Melanoma and BRAF V600E mutation?

From the Guidelines

Yes, the low TSH level (less than 0.1) in this 30-year-old male with melanoma could be related to his BRAF/MEK inhibitor therapy with Cobimetinib (Cotellic) and Vemurafenib (Zelboraf). Thyroid dysfunction, particularly hyperthyroidism, is a known adverse effect of these medications. The combination of Vemurafenib and Cobimetinib has been associated with thyroid function abnormalities in approximately 5-20% of patients, as reported in the NCCN guidelines 1. The mechanism involves the MAPK pathway, which these drugs target to treat the BRAF V600E-mutated melanoma, but this pathway also plays a role in thyroid hormone regulation.

Key Points to Consider

• The patient should undergo further thyroid function testing, including free T4 and T3 levels, to confirm hyperthyroidism.
• If hyperthyroidism is confirmed, the patient may require monitoring or treatment depending on symptom severity, but typically the thyroid dysfunction is mild and may not require discontinuation of the cancer therapy.
• Regular thyroid function monitoring (every 4-8 weeks) is recommended for patients on BRAF/MEK inhibitor therapy, especially during the first few months of treatment when these changes are most likely to occur, as suggested by the NCCN guidelines 1.
• The most recent guidelines from ASCO also emphasize the importance of monitoring for toxicity, including thyroid dysfunction, in patients receiving BRAF/MEK inhibitor therapy 1.

Recommendations for Management

• Close monitoring of thyroid function is crucial in patients on BRAF/MEK inhibitor therapy.
• Patients should be educated on the signs and symptoms of thyroid dysfunction and the importance of reporting any changes to their healthcare provider.
• The decision to continue or modify the cancer therapy should be made on a case-by-case basis, considering the benefits and risks of treatment, as well as the patient's overall health status and preferences.

From the Research

Thyroid Dysfunction and Medication

• The patient's recent lab results showing a TSH level less than 0.1 may be related to the medications Cobimetinib (Cotellic) and Vemurafenib (Zelboraf) used to treat Melanoma with BRAF V600E mutation(s) 2.
• However, the provided studies do not directly link these medications to thyroid dysfunction.
• Other conditions and some drugs can be associated with a TSH level that is slightly low (0.1-0.4 microIU/mL) or frankly suppressed (< 0.1 microIU/mL) 2.

Immune Checkpoint Inhibitors and Thyroid Dysfunction

• Checkpoint inhibitors, such as ipilimumab, nivolumab, and pembrolizumab, used in the treatment of melanoma, are associated with a high rate of immune side effects, including endocrinopathy 3.
• Thyroid dysfunction occurs commonly in patients with melanoma treated with immune checkpoint inhibitors, with rates, including subclinical dysfunction, occurring in up to 50% 3.
• Pembrolizumab, an anti-programmed cell death 1 (PD-1) receptor monoclonal antibody, is associated with thyroid dysfunction, including thyrotoxicosis and hypothyroidism 4.

Management of Thyroid Dysfunction

• The management of patients with persistent symptoms despite normal thyroid function tests, and potential new innovations in thyroid hormone therapy, are important considerations 5.
• The diagnosis of subclinical hypothyroidism should be confirmed by repeat thyroid function tests, and treatment is not necessary unless the TSH exceeds 7.0-10 mIU/L 6.
• TSH goals are age-dependent, and combined treatment with levothyroxine and liothyronine may be preferred in some hypothyroid patients who are dissatisfied with treatment 6.