Familial Status Modulates the Stability of Excellent Response in Non-Medullary Thyroid Carcinoma: Implications for Tailored Surveillance

Background: The clinical impact of familial history on the prognosis of non-medullary thyroid cancer (NMTC) remains controversial. This study aimed to investigate whether familial NMTC (fNMTC) is associated with different patterns of response-to-therapy evolution over time compared to sporadic NMTC (sNMTC), using a dynamic risk stratification (DRS) approach. Methods: We analyzed 665 sNMTC cases and 130 fNMTC cases. Response to therapy was assessed at the first follow-up (6–12 months after initial therapy) and at the last outcome. Univariate and multivariate analyses were used to assess the role of family history as a modifier of response reclassification, independently of established prognostic factors. Results: A significant difference in the dynamic pattern of response evolution was observed between fNMTC and sNMTC (p = 0.003), with familial cases showing higher response variability. Among patients with an initial excellent response (n = 558), familial status remained the only independent predictor of losing excellent response (OR 3.3, 95% CI 1.54–7.12; p = 0.002). The worsening in fNMTC was primarily driven by transitions to indeterminate or biochemical incomplete responses (12.3% vs. 4.2%, p = 0.006), while structural progression remained rare and similar between groups (2.5% vs. 1.3%, p = 0.33). Regarding recovery, 50.2% of patients with an initial non-excellent response achieved an excellent response, with no significant difference between familial and sporadic cases (61.2% vs. 47.3%, p = 0.1). An intermediate-to-high ATA risk class was independently associated with a lower probability of achieving an excellent response (OR 0.45, 95% CI 0.25–0.91; p = 0.01). Conclusions: These findings suggest that “Excellent Response” is more fragile in a familial context. Familial NMTC might require prolonged and vigilant biochemical surveillance, even when cases appear to be in full remission.