Deep response to a combination of mTOR inhibitor temsirolimus and dual immunotherapy of nivolumab/ipilimumab in poorly differentiated thyroid carcinoma with PTEN mutation: a case report and literature review

Abstract

Treating advanced thyroid cancer presents challenges due to its resistance to various treatment modalities, thereby limiting therapeutic options. To our knowledge, this study is the first to report the efficacy of temsirolimus in conjunction with dual immunotherapy of nivolumab/ipilimumab to treat heavily treated advanced PDTC. A 50-year-old female initially presented with a rapidly enlarging mass on her right neck. Subsequent diagnosis revealed poorly differentiated thyroid carcinoma, leading to a total thyroidectomy followed by post-operative radioablation therapy. After four years, an examination for persistent cough revealed a recurrence of the disease within multiple mediastinal nodes. Genetic analysis of blood samples uncovered somatic mutations in the tumor, specifically involving PTEN and TP53. The disease progressed despite palliative radiation, lenvatinib, and nivolumab/ipilimumab therapy. Consequently, temsirolimus, functioning as an mTOR inhibitor, was introduced as an adjunct to the nivolumab/ipilimumab regimen. This combination approach yielded remarkable clinical improvement and disease control for a duration of approximately six months. Temsirolimus likely suppressed the aberrantly activated PI3K/AKT/mTOR signaling pathway, facilitated by the PTEN genetic alteration, thus engendering an effective treatment response. This synergy between targeted agents and immunotherapy presents a promising therapeutic strategy for advanced PDTC patients with limited treatment alternatives. In previous clinical trials, mTOR inhibitors have demonstrated the ability to maintain stable disease (SD) in 65% to 74% for advanced thyroid cancer patients, including those with PDTC. When combined with other targeted therapies, the observed SD or partial response rates range from 80% to 97%. Many of these trials primarily involved differentiated thyroid carcinoma, with diverse genetic mutations. Thyroid cancer patients with alterations in the PI3K/mTOR/Akt appeared to benefit most from mTOR inhibitors. However, no clear association between the efficacy of mTOR inhibitors and specific histologies or genetic mutations has been established. Future studies are warranted to elucidate these associations.

The Long Journey towards Personalized Targeted Therapy in Poorly Differentiated Thyroid Carcinoma (PDTC): A Case Report and Systematic Review

“…Since cytological diagnosis of PDTC based on FNAC is challenging, our review has shown that some patients underwent a hemithyroidectomy or subtotal thyroidectomy with a completion thyroidectomy after histological diagnosis [ 38 , 44 , 52 , 54 , 59 , 65 , 69 , 85 , 103 , 104 , 107 , 108 , 115 , 117 ], but the majority of them were submitted to a total thyroidectomy as the initial operation [ 40 , 41 , 42 , 43 , 46 , 48 , 49 , 50 , 51 , 53 , 54 , 55 , 56 , 58 , 60 , 61 , 62 , 64 , 67 , 68 , 69 , 72 , 73 , 75 , 79 , 80 , 81 , 82 , 85 , 86 , 88 , 89 , 90 , 91 , 92 , 93 , 95 , 96 , 100 , 101 ,…”

“…Unlike in DTC [ 123 , 124 ], RAI appears to be relatively ineffective in the control of distant metastases in PDTC; thus, it is reasonable to consider the use of RAI for metastatic/advanced disease that demonstrates definite iodine uptake [ 125 , 126 ]. Likewise, most cases in our review received at least one cycle of RAI treatment, even without detectable metastatic foci [ 38 , 39 , 40 , 41 , 42 , 43 , 46 , 48 , 49 , 50 , 51 , 53 , 54 , 55 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 73 , 74 , 75 , 80 , 81 , 82 , 85 , 86 , 87 , 88 , 90 , 91 , 97 , 99 , 101 , 102 , 104 , 105 , 106 , 107 , 108 , 109 , 110 , 111 ...…”

“…In our case report, RAIR disease was evident after two RAI treatments. External beam radiation therapy (EBRT) is a viable option for controlling local disease in patients with PDTC and was utilized in the subset of patients with unresected, locally advanced disease or with metastatic foci such as bone lesions [ 42 , 49 , 50 , 58 , 60 , 61 , 62 , 63 , 64 , 67 , 68 , 69 , 70 , 74 , 75 , 80 , 81 , 85 , 90 , 91 , 97 , 98 , 102 , 106 , 107 , 108 , 109 , 112 , 113 , 116 ].…”

“…In the majority of studies in our review, the extent of the poorly differentiated area was not reported, and a PDTC definition was decided to address this component. A large number of patients with PDTC reviewed herein presented with locally advanced disease (T3 or T4, extrathyroidal extension, and nodal involvement) [ 40 , 44 , 46 , 47 , 49 , 50 , 51 , 54 , 55 , 57 , 58 , 60 , 61 , 62 , 64 , 67 , 68 , 69 , 70 , 71 , 73 , 74 , 75 , 76 , 77 , 78 , 80 , 81 , 82 , 83 , 84 , 85 , 86 , 87 , 88 , 90 , 91 , 92 , 94 , 97 , 98 , 99 , 100 , 101 , 102 , 107 , 108 , 109 , 111 , 112 , 113 , 114 , 115 , 116 ,…”

“…This was based on two seminal phase 3 trials (DECISION and SELECT, respectively), which included a limited number of PDTC cases, with the respective subgroup analyses available in the appendix of the studies [ 147 , 148 ]. In fact, in the cases discussed herein, TKIs, especially lenvatinib and sorafenib, were widely used in metastatic disease [ 42 , 44 , 50 , 55 , 60 , 67 , 68 , 73 , 75 , 80 , 81 , 84 , 89 , 90 , 94 , 98 , 109 , 110 , 111 ]. The actual benefit in terms of patient survival remains to be seen, since, in some patients, control was obtained [ 42 , 44 , 64 , 67 , 73 , 80 , 81 , 84 , 97 , 110 ], while others succumbed to the disease [ 55 , 60 , 86 , 89 , 90 , 94 , 97 , 98 , 109 , 111 ].…”