Study Suggests Role for Anti-PD-1/PD-L1 Agents in Advanced Thyroid Cancer

Results of a retrospective Chinese study suggest that among patients with medullary thyroid cancer (MTC), PD-L1 positive status is linked to more aggressive clinicopathological features and predictive of structural and biochemical recurrences.

The investigators are hopeful that these findings indicate that PD-1/PD-L1 inhibitors would be a successful therapeutic option for patients with PD-L1—positive advanced MTC.

Prior research into PD-L1 expression in thyroid malignancies focused on follicular histology, and those studies that did investigate MTC did not provide sufficient evidence on the prognostic significance of positive expression.“…To the best of our knowledge, this is the first study to demonstrate the correlation of PD-L1 positivity with [structural recurrence] and [biochemical recurrence/persistent disease] in MTC,” the study authors wrote in their report published in Thyroid.

For the retrospective analysis, 201 patients with MTC who were surgically treated at the Fudan University Shanghai Cancer Center between January 2006 and December 2015. The median follow-up was 73 months (range, 2-153).

Across all patients, the median age at diagnosis was 49 (range, 12-80), 52.7% were male, 85.6% did not have a hereditary cancer, and 82.1% had concomitant Hashimoto’s thyroiditis. A majority (57.2%) had tumors that were smaller in size (≤2 cm), 51.7% had AJCC/TNM stage IV disease, and most had lymph node metastasis, especially in the lateral neck (42.8%), although none of the patients had distant metastasis at diagnosis. Biochemical recurrence or persistent disease developed in 49.3% of patients and 6.0% died as a result of their disease.

The Dako PD-L1 IHC 22C3 pharmDx assay was used to evaluate PD-L1 status, which was measured by combined positive score (CPS), defined as the ratio of PD-L1—stained cells (tumor cells, lymphocytes, and macrophages) among the total number of viable tumor cells that was then multiplied by 100. Patients were then divided into expression groups based on the CPS levels: CPS 1 to <5, low; CPS 5 to <20, moderate; and CPS ≥20, high.

Twenty-nine (14.4%) patients had positive PD-L1 expression. Of these patients, 7 had low expression and another 7 had high expression.

The median age at diagnosis for the 29 PD-L1—positive patients was 49 (range, 32-73), 62.1% were male, 86.2% did not have a hereditary cancer, and 86.2% had concomitant Hashimoto’s thyroiditis. Most (61.2%) had tumors between 2.1 and 4 cm, 65.5% had lateral neck lymph node metastasis, and 75.9% had AJCC/TNM stage IV disease. Twenty-two patients (75.9%) developed biochemical recurrence/persistent disease and 4 (13.8%) died as a result of MTC.

Characteristics associated with PD-L1 positivity include a larger tumor size (P = .002), lymph node metastasis (P = .036), TNM staging (P = .019), structural recurrence (P = .006), and biochemical recurrence/persistent disease (P = .002).

“Our results show that PD-L1—positive MTC is positively associated with a larger tumor size, lymph node metastasis, as well as more advanced TNM staging, indicating that these patients tend to have a higher preoperative tumor burden,” the investigators wrote.

Using multivariate Cox analysis, the investigators determined that a higher level of lymph node metastasis, higher postoperative basal serum calcitonin levels, and PD-L1 positivity were all independently associated with structural recurrence, increasing the risk of recurrence in patients with MTC. Additionally, larger tumor sizes, multifocal disease, lymph node metastasis, and positive PD-L1 expression were all independently associated with biochemical recurrence/persistent disease, increasing the odds of recurrence or persistent disease.

Positive PD-L1 expression was an independent predictor of structural recurrence (HR, 2.17; P = .039) as well as biochemical recurrence/persistent disease (odds ratio [OR], 3.09; P = .014).

The rate of structural recurrence-free survival (SRFS) at 5 years in the overall population was 81.6%. PD-L1—positive patients had a 5-year SRFS rate of 57.9% compared with 85.4% in PD-L1–negative patients (P = .001). In patients with positive PD-L1 expression specifically, the 5-year SRFS rates were 84.2%, 72.4%, and 34.3% in those with negative/low, moderate, and high expression, respectively.

The difference between the high and negative/low expression groups was statistically significant (P = .001); however, the difference between the negative/low and moderate groups (P = .286) as well as between the moderate and high groups (P = .084) did not meet statistical significance. The study authors noted that this lack of significance could have been a result of the small sample size of patients with PD-L1 positivity.

Following initial surgery (median follow-up, 23 months) distant or unresectable locoregional recurrence was detected in 20 cases in follow-up. Of these patients, half were male, 95% had stage IVA disease, 10% had had a prior recurrence, 60% had PD-L1 positivity, and 40% were still alive as of data cutoff.

“The increased tumor aggressiveness and recurrence risk of the PD-L1—positive disease may explain the higher positive rate [of PD-L1 expression] in advanced disease, which suggests a potential for PD-1 blockade in the treatment of late-stage MTC,” the study authors noted.

In their report, the investigators acknowledged that the efficacy of PD-1/PD-L1 immune checkpoint inhibitors are not only influenced by PD-L1 expression and noted that the potential of immunotherapy to treat patients with PD-L1—positive MTC required formal demonstration in clinical trials.

Shi X, Yu PC, Lei BW, et al. Association between programmed death-ligand 1 expression and clinicopathological characteristics, structural recurrence, and biochemical recurrence/persistent disease in medullary thyroid carcinoma [published August 19, 2019]. Thyroid. doi: 10.1089/thy.2019.0079.