Risk Of Second Malignancies Research Articles

Associations of radiotherapy receipt with lung cancer risk by histological subtype among breast cancer survivors in the United States.

Radiotherapy for breast cancer has been associated with an increased risk of secondary malignancies, including primary lung cancer. Whether this association varies by histological subtype of lung cancer remains unknown. Based on the data from 12 Surveillance, Epidemiology, and End Results registries, we examined the association between radiotherapy receipt and the risk of subtype-specific subsequent primary lung cancer (SPLC) among female first primary breast cancer cases diagnosed between ages 20 and 84 from 1992 to 2020. More than half (53%) of the 550,007 breast cancer survivors identified had undergone radiotherapy as part of their initial breast cancer treatment. Over an average follow-up of 9.7 years, 8014 survivors developed SPLCs. For small-cell carcinoma, the standardized incidence ratio (SIR) compared with the general population was higher for survivors who received radiotherapy (SIR = 1.15, 95% confidence interval [CI] = 1.06-1.25) but similar for those who did not receive radiotherapy (SIR = 1.00, 95% CI = 0.91-1.09), with the difference in SIRs being statistically significant (p = .003). Similar associations were found for squamous cell carcinoma (SIRyes = 1.16, 95% CI = 1.08-1.24 vs. SIRno/unknown = 1.06, 95% CI = 0.98-1.15; p = .07). The increased risks were confined to ipsilateral SPLC, with the greatest SIRs for small-cell carcinoma occurring 5-10 years since breast cancer diagnosis (SIR = 1.83, 95% CI = 1.53-2.19) and for squamous cell carcinoma with a latency of 10 years or more (SIR = 1.64, 95% CI = 1.42-1.88). In contrast, the risk of developing adenocarcinoma did not vary by radiotherapy receipt (SIRyes = 1.23, 95% CI = 1.18-1.28 vs. SIRno/unknown = 1.17, 95% CI = 1.12-1.22; p = .18), indicating additional risk factors in play. The findings suggest a distinct carcinogenic pathway of radiation-induced lung cancer across histological subtypes and may inform risk-stratified surveillance guidelines for SPLC.

Characteristics and outcomes of therapy-related acute leukemia following autologous transplant (Auto-HCT) for multiple myeloma.

With a prolonging duration of survivorship, patients with multiple myeloma (MM) who receive high-dose chemotherapy and autologous hematopoietic stem cell transplantation (auto-HCT) have an increased risk of secondary malignancy, most concerning acute leukemia. We retrospectively reviewed the records of all patients with MM who underwent auto-HCT between January 1, 2010, and January 1, 2023, who later developed therapy-related acute leukemia (t-AL). Of 1770 patients with MM who underwent auto-HCT, 18 (1.01%) developed t-AL at a mean interval of 60.0 ± 41.3 months after auto-HCT. The patients with t-AL consisted of 9 (50%) with B-cell acute lymphoblastic leukemia (B-ALL), 8 (44.4%) with acute myeloid leukemia (AML), and 1 (5.6%) with acute promyelocytic leukemia (APML). All patients had received an alkylating agent as part of induction, and the majority received lenalidomide as maintenance therapy. Genetic abnormalities of t-AL were consistent with prior reports. Median overall survival from diagnosis of t-AL was 19.5 months. In patients with t-AL who entered CR, long term survival was common. Further research on predisposing conditions to developing t-AL in patients with MM undergoing auto-HCT is warranted.

Stage-dependent treatment of seminomas

Germ cell neoplasms of the testis are rare solid tumors predominantly in young men. Seminomas are slightly more frequent than nonseminomatous germ cell tumors. A special feature of seminomas is that they are sensitive to radiation, so that this represents an option in tumor stages with few metastases; however, the guideline recommendation is cautious due to the increased risk of secondary malignancies. In nonmetastasized tumor stages active surveillance is the primary approach to avoid overtreatment of patients. This is also the reason for primary nerve-sparing retroperitoneal lymph node dissection in cases of a low metastasis load. This concept has already been implemented in the American Urological Association (AUA) and National Comprehensive Cancer Network (NCCN) guidelines, whereas in the European Association of Urology (EAU) guidelines it is still considered to be an individual approach.

EP.07G.07 Risk and Outcomes of Secondary Malignancy Among Non-Small Cell Lung Cancer Survivors Following Definitive Treatment

EP.07G.07 Risk and Outcomes of Secondary Malignancy Among Non-Small Cell Lung Cancer Survivors Following Definitive Treatment

Assessment of secondary cancer risks within non-target organs during proton therapy for lung cancer: A Monte Carlo study

Proton therapy is a rapidly progressing modality with a significant impact on lung cancer treatment. However, there are concerns about the subsequent effects of secondary radiation in out-of-field organs. Thus, the present study aimed to evaluate the risk of subsequent secondary cancers within non-target organs during proton therapy for lung cancer. A Monte Carlo model of the International Commission on Radiological Protection (ICRP) 110 male phantom was employed to calculate the absorbed dose associated with secondary photons and neutrons within out-of-field organs for different tumor locations. The risk of induced secondary cancers was then estimated using the Biological Effects of Ionizing Radiation Committee (BEIR) VII and National Council on Radiation Protection and Measurements (NCRP) 116 risk models. Organs close to the tumor, such as the heart, esophagus, thymus, and liver, received the highest equivalent doses. The calculated equivalent doses increased as the tumor depth increased from 4–8 cm to 12–16 cm. The contribution of neutrons to the total equivalent dose was dominant (up to 90%) in most of the organs studied. The calculated risks of secondary cancers were higher in the liver and esophagus compared with other organs when using the BEIR risk model. The maximum risk value was obtained for the left lung when the NCRP 116 risk model was used. Furthermore, the estimated risks of secondary malignancies increased with the tumor depth using both risk models. The calculated risks of radiation-induced secondary cancers were relatively lower than the baseline cancer risks. However, extra attention is warranted to minimize subsequent secondary cancers after proton therapy for lung cancer.

Longitudinal needs and cancer knowledge in Swiss childhood cancer survivors transitioning from pediatric to adult follow-up care: results from the ACCS project

PurposeChildhood Cancer Survivors (CCSs) have an increased risk for treatment-related chronic health conditions, but the adherence to long-term follow-up (LTFU) care decreases over time. We therefore assessed the CCSs’ development of cancer knowledge, cancer worries, self-management skills, and expectations for LTFU care in a structured, cancer center-based transition model—a crucial part for maintaining adherence.MethodsUsing questionnaire-based surveys, we compared the CCSs’ cancer knowledge with medical record data and assessed cancer worries (6 questions), self-management skills (15 questions), and expectations (12 questions) longitudinally by validated scales. We used descriptive statistics for presenting our results.ResultsWe analyzed 17 CCSs, 71% were female, had a median age of 8 years at diagnosis and 21 years at study enrollment. The knowledge about late effects increased during the transition process, except for the risk of secondary malignancies. Leukemia survivors had a decrease in cancer worries. At least 75% of the CCSs agreed to 11 of 15 self-management questions before and after transition, with the highest increase over time in less parental involvement. The CCSs expected the most, that physicians know the CCSs’ cancer history, that the visit starts on time, and that physicians can always be called in case of questions.ConclusionsOur transition model improved cancer knowledge, especially the risk for late effects, decreased cancer worries, and identified expectations for LTFU care which should be considered in the future. A structured transition process with evidence-based tools further increases the knowledge of CCS for LTFU through empowerment.

Development of an external system for monitoring the couch speed in radiotherapy using continuous bed movement.

Total body irradiation before bone marrow transplantation for hematological malignancies using Radixact, a high-precision radiotherapy machine, can potentially reduce side effects and the risk of secondary malignancies. However, stable control of couch speed is critical, and direct assessment methods outlined in quality assurance guidelines are lacking. This study aims to develop a real-time couch speed verification system for the Radixact. The developed system used a linear encoder to measure couch speed directly. Accuracy was verified via a linear stage, comparing measurements with a laser distance sensor. After placing a phantom simulating the human body on the Radixact couch, the couch speed was verified using predefined speed plans. Operating the linear stage at 0.1, 0.5, and 1.0mm/s revealed that the maximum position error of the developed verification system compared to the laser distance sensor was nearly equivalent to the distance resolution of the system (0.05mm/pulse), with negligible average speed error. When the Radixact couch operated at 0.1, 0.5, and 1.0mm/s, the values obtained by the verification system agreed with the theoretical values within the sampling period (0.01s) and distance resolution (0.05mm). The verification system developed provides real-time monitoring of the speed of the Radixact table, ensuring treatment effectiveness and patient safety. It would guarantee the couch speed's soundness and contribute to the "visualization" of safety.

Safety assessment of anti-B cell maturation antigen chimeric antigen receptor T cell therapy: a real-world study based on the FDA adverse event reporting system database.

On April 18, 2024, the U.S. Food and Drug Administration officially required updating of the "boxed warning" for T cell malignancies for all chimeric antigen receptor T cell (CAR-T) therapies. Given the clinical significance of these therapies, a rigorous safety assessment is paramount. However, comprehensive real-world safety studies have been lacking for the newly marketed CAR-T products idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel (cilta-cel), which target B cell maturation antigen, especially regarding the risk of secondary malignancies. Therefore, we aimed to thoroughly analyze the adverse events (AEs) information in the FDA Adverse Event Reporting System (FAERS) database to comprehensively understand the safety risks of ide-cel and cilta-cel. We extracted AE reports related to ide-cel and cilta-cel from the FAERS database (https://fis.fda.gov/extensions/FPD-QDE-FAERS/FPD-QDE-FAERS.html.) from January 1, 2019 to December 31, 2023. Disproportionality analysis and Bayesian analysis were used to identify risk signals across subgroups and specific cases (including for death and secondary malignancies). Weibull distribution analysis was employed to determine the time to AE onset. A total of 695 AE reports for ide-cel and 848 for cilta-cel were included in the FAERS database. This analysis identified 81 positive signals for ide-cel and 74 for cilta-cel. Notably, comparisons with the drug labels revealed "unexpected signals," including febrile bone marrow aplasia (reporting odds ratio=69.10; confidence interval 39.12-122.03) and plasma cell myeloma (12.45; 8.18-18.95) for ide-cel, and increased serum ferritin (24.98; 8.0-77.58) and large intestine perforation (18.57; 5.98-57.69) for cilta-cel. Both drugs showed a higher AE incidence among male recipients and patients aged ≥65 years, although female recipients faced a greater risk. Most AEs occurred at the early stage of administration. However, secondary malignancies were detected for both drugs, primarily occurring one-year post-administration. This study provides a foundation for understanding the safety profile of CAR-T cell therapy, particularly in relation to the emergence of secondary malignancies. Such insights are helpful for clinical decision-making and the safe and effective utilization of these therapeutic agents.

Stereotactic Radiation Therapy for Localized Prostate Cancer: 10-Year Outcomes From Three Prospective Trials

Background and purposeStereotactic ablative radiotherapy (SABR) is growingly accepted for the treatment of localized prostate cancer with recent randomized trials showing non-inferiority compared to conventional or moderately hypofractionated radiotherapy. The natural history of prostate cancer necessitates extended surveillance for recurrence; however, there are few prospective studies reporting long-term outcomes. Materials and methodsThis study included patients with low and intermediate risk localized prostate cancer from three Canadian clinical trials enrolled from 2006-2013. All patients received SABR to the prostate consisting of 35-40 Gy in 5 fractions over 11-29 days. PSA, distant metastasis, and vital status were prospectively recorded. Occurrence of second malignancy after treatment was assessed by chart review and classified using modified Cahan's criteria. Results267 patients were included. Median follow up was 10.3 years (IQR 7.8 – 12.7). 10-year BF (95% CI) was 7.7% (3.9-11.5). 10-year OS, PCSS, and FFM were 84.1% (79.3 – 89.1%), 99.2% (98.1 – 100), and 98.8% (97.5-100), respectively. 27/267 (10.1%) patients experienced a SM, with 6/27 patients (22.2%) classified as having a SM likely (n=3) or possibly (n=3) related to prior radiotherapy. 10-year freedom from SM was 89.2%. ConclusionSABR shows excellent long-term disease control for low and intermediate risk localized prostate cancer. Patients treated for prostate cancer have a moderate risk of second malignancy, consistent with background rates for the population.

The Current Landscape of Secondary Malignancies after CAR T-Cell Therapies: How Could Malignancies Be Prevented?

Chimeric antigen receptor (CAR) T-cell therapies have revolutionised the field of haematological malignancies by achieving impressive remission rates in patients with highly refractory haematological malignancies, improving overall survival. To date, six commercial anti-CD19 and anti-BCMA CAR T-cell products have been approved by the Food and Drug Administration (FDA) for the treatment of relapsed/refractory B-cell haematological malignancies and multiple myeloma. The indications for CAR T-cell therapies are gradually expanding, with these therapies being investigated in a variety of diseases, including non-malignant ones. Despite the great success, there are several challenges surrounding CAR T-cell therapies, such as non-durable responses and high-grade toxicities. In addition, a new safety concern was added by the FDA on 28 November 2023 following reports of T-cell malignancies in patients previously treated with either anti-CD19 or anti-BCMA autologous CAR T-cell therapies both in clinical trials and in the real-world setting. Since then, several reports have been published presenting the incidence and analysing the risks of other secondary malignancies after CAR T-cell therapies. In this opinion article, the current landscape of secondary malignancies after CAR T-cell therapies is presented, along with a proposed strategy for future research aiming at potentially diminishing or abrogating the risk of developing secondary malignancies after CAR T-cell therapies.

The risk of second malignancies following prostate cancer radiotherapy in the era of conformal radiotherapy: astatement of the Prostate Cancer Working Group of the German Society of Radiation Oncology (DEGRO).

Asignificant number of prostate cancer patients are long-term survivors after primary definitive therapy, and the occurrence of late side effects, such as second primary cancers, has gained interest. The aim of this editorial is to discuss the most current evidence on second primary cancers based on six retrospective studies published in 2021-2024 using large data repositories not accounting for all possible confounding factors, such as smoking or pre-existing comorbidities. Overall, prostate cancer patients treated with curative radiotherapy have an increased risk (0.7-1%) of the development of second primary cancers compared to patients treated with surgery up to 25years after treatment. However, current evidence suggests that the implementation of intensity modulated radiation therapy is not increasing the risk of second primary cancers compared to conformal 3D-planned radiotherapy. Furthermore, increasing evidence indicates that highly conformal radiotherapy techniques may not increase the probability of second primary cancers compared to radical prostatectomy. Consequently, future studies should consider the radiotherapy technique and other confounding factors to provide amore accurate estimation of the occurrence of second primary cancers.

High Risk of Transformation and Secondary Malignancies in Follicular Lymphoma Patients Treated With First-Line Bendamustine Rituximab and Rituximab Maintenance

High Risk of Transformation and Secondary Malignancies in Follicular Lymphoma Patients Treated With First-Line Bendamustine Rituximab and Rituximab Maintenance

IBCL-550 High Risk of Transformation and Secondary Malignancies in Follicular Lymphoma Patients Treated With First-line Bendamustine Rituximab and Rituximab Maintenance

IBCL-550 High Risk of Transformation and Secondary Malignancies in Follicular Lymphoma Patients Treated With First-line Bendamustine Rituximab and Rituximab Maintenance

Prevalence of malignant neoplasms in celiac disease patients - a nationwide United States population-based study.

Celiac disease (CeD) is an autoimmune disorder triggered by the immune response to gluten in genetically predisposed individuals. Recent research has unveiled a heightened risk of developing specific malignant neoplasms (MN) and various malignancies, including gastrointestinal, lymphomas, skin, and others, in individuals with CeD. To investigate the prevalence of MN in hospitalized CeD patients in the United States. Using data from the National Inpatient Sample spanning two decades, from January 2000 to December 2019, we identified 529842 CeD patients, of which 78128 (14.75%) had MN. Propensity score matching, based on age, sex, race, and calendar year, was employed to compare CeD patients with the general non-CeD population at a 1:1 ratio. Positive associations were observed for several malignancies, including small intestine, lymphoma, nonmelanoma skin, liver, melanoma skin, pancreas myelodysplastic syndrome, biliary, stomach, and other neuroendocrine tumors (excluding small and large intestine malignant carcinoid), leukemia, uterus, and testis. Conversely, CeD patients exhibited a reduced risk of respiratory and secondary malignancies. Moreover, certain malignancies showed null associations with CeD, including head and neck, nervous system, esophagus, colorectal, anus, breast, malignant carcinoids, bone and connective tissues, myeloma, cervix, and ovary cancers. Our study is unique in highlighting the detailed results of positive, negative, or null associations between different hematologic and solid malignancies and CeD. Furthermore, it offers insights into evolving trends in CeD hospital outcomes, shedding light on advancements in its management over the past two decades. These findings contribute valuable information to the understanding of CeD's impact on health and healthcare utilization.

CAR T-cell therapies: risk of secondary malignancy of T-cell origin

CAR T-cell therapies: risk of secondary malignancy of T-cell origin

Dose equivalent consideration from neutron contamination in modified radiotherapy vault: a Monte Carlo study

Laminated barriers incorporating metal sheets provide effective protection for space-restricted radiotherapy centers. This study aimed to assess photoneutron contamination in smaller vaults protected by different compositions of multilayer barriers during simulated pelvic radiotherapy with 18 MV photon beams. Monte Carlo Simulations of 18 MV LINAC (Varian 2100 C/D) and Medical Internal Radiation Dose (MIRD) phantom were used to assess photoneutron contamination within reconstructed vaults incorporating different combinations of metal sheet and borated polyethylene (BPE) during pelvic radiotherapy. The findings highlight a 3.27 and 2.91 times increase in ambient neutron dose Hn* (10) along the maze of reconstructed vaults that use lead and steel sheets, respectively, compared to concrete. The Hn* (10) outside the treatment room increased after incorporating a metal sheet, but it remained within the permissible limit of 20 μSv/week for uncontrolled areas adjacent to the LINAC bunker, even with a workload of 1000Gy/week. Neutron equivalent doses in the patient’s organs ranged from 0.22 to 0.96 mSv Gy−1. There is no notable distinction in the organ’s neutron equivalent dose, fatal cancer risk, secondary radiation-induced cancer risk, and cancer mortality for various laminated barrier compositions. Furthermore, the use of metal sheets for vault wall reconstruction keeps the variation in cancer risk induced by photoneutrons below 6%, while risks of fatal cancer and cancer mortality vary less than 11%. While the metal portion of the laminated barrier raises the neutron dose, the addition of a BPE plate reduces concerns of increased effective dose and secondary malignancy risk.

Maintenance therapy after Autologous Stem Cell Transplantation in Multiple Myeloma – currents and perspectives

MM is non-curable cancer that arises from plasma cells and is the second most common type of blood cancer. Drug-refractory relapses are inevitable, making it essential to sustain long-lasting remissions as part of therapy. Lenalidomide maintenance until progression is a standard of care for transplant-eligible newly-diagnosed patients. However, poor outcomes of high-risk patients and the risk of secondary primary malignancies associated with maintenance underline the need for novel approaches. Significant changes in frontline treatment maintenance are expected, with the increasing importance of minimal residual disease monitoring and the development of novel drug combinations for maintenance. This article explores current standards and prospects for maintaining response after upfront in ASCT in MM.

Trends in mortality from secondary malignancy in the United States, 1999-2019.

11166 Background: Recent advancements in cancer diagnosis, treatment, and supportive care increased the survivorship of cancer patients. However, the risk of secondary malignancy (SM), associated most commonly with side effects of radiation and chemotherapies, has emerged as a looming threat to childhood and adult-onset cancer survivors. Recognizing the recent trends in malignancy-related deaths and the risk factors associated could assist healthcare professionals and policymakers in constructing appropriate guidelines for timely diagnosis and individual patient-dependent treatment regimens. Hence, our CDC analysis focuses on highlighting trends in mortality from SM from “1999 to 2019”. Methods: Using the deidentified death certificate data from the CDC WONDER database, we analyzed mortality trends from 1999 to 2019 for SM. Age-adjusted mortality rates (AAMRs) per 100,000 people were calculated for the total population, stratified by gender, race, age, and site of SM. Annual percent change (APC) was calculated using the Joinpoint regression software. Results: A total of 1,499,108 deaths occurred from 1999 to 2019 in the US. The overall AAMR showed a decrease from 27.5 in 1999 to 18.83 in 2007 (APC: -4.71), remained at a relatively constant level of 19.11 till 2013 (APC: 0.48), followed by a rapid rise to 23.29 in 2017 (APC: 5.37), and finally a gradual rise to 24.29 in 2019 (APC: 1.97). Men showed consistently higher AAMR than women throughout the study period between 1999 (AAMR Men: 33.31 vs Women: 23.78) and 2019 (AAMR Men: 28.03 vs Women: 21.51). Moreover, Black (AAMR: 23.89) showed the highest mortality rate, followed by Whites (AAMR: 21.46). American Indian (AAMR: 13.93), Asian (AAMR: 13.89), and Hispanic (AAMR: 15.9) showing similar mortality trends. Furthermore, AAMR increased with age, showing the highest mortality rates in patients 75+ yrs (148.3), followed by 55-74 yrs (61.6), 35-54 yrs (9.23), 15-34 yrs (0.7), and ≤ 14 yrs (0.19). More recently the greatest rise in SM from 2013-2019 was observed in adrenal glands (APC: 11.8), bone and bone marrow (APC: 8.7), kidney and renal pelvis (APC: 7.6), and small intestine (APC: 6.9). Less prominent rise was seen in all other types of SM. Conclusions: Despite recent advances in cancer treatments, SM remains one of the most common causes of death in cancer survivors. Our analysis shows that age, gender, race, and site are important factors influencing the risk of SM-related mortality. Although the risk of SM varies across the spectrum of age, findings from one age group could be translated into preventive and screening strategies across other age groups. Guidelines for survivors should be taken into account based on prior treated malignancy and the risk of future ones. Large population based studies are imperative to understand factors behind the recent rise in SM-related mortalities from 2013 onwards.

Risk of secondary leukemias in patients with germline PALB2 pathogenic variants after chemotherapy exposure.

10598 Background: Pathogenic variants in germline cancer-predisposing genes (e.g. BRCA1/2, PALB2) confer an increased risk for solid tumors but not de novomyeloid malignancies. Many of these genes are related to DNA repair pathways. It is not known whether exposure to genotoxic therapy increases the risk of secondary hematologic malignancies. Here, we report the incidence of hematologic malignancy after a solid tumor diagnosis among patients with a germline PALB2 pathogenic variant. Methods: Patients were identified at the Massachusetts General Hospital Center for Cancer Risk Assessment among individuals seeking counseling and/or testing for hereditary cancer risk genes. Analyses were conducted using R version 4.2.2 “tidyverse” and “gtsummary” packages. Results: Of the 176 charts reviewed, 102 (57%) had a history of malignancy, of which 68 (66%) received genotoxic chemotherapy. The median follow-up after chemotherapy was 59mo (IQR =17,109). The most common malignancy and chemotherapy were breast cancer (n=76, 75%) and doxorubicin, cyclophosphamide, and paclitaxel (n = 21, 31%). We compared patient outcomes by receipt of chemotherapy or not. There was no difference in race, age at cancer diagnosis, surgery rate, treatment with hormone therapy, or secondary malignancy between the two groups (p > 0.05). There was higher incidence of radiation treatment in those receiving genotoxic therapy compared to those who did not (65% vs 41%, p = 0.024), but no difference Gray or in follow up after radiation. Mortality in the genotoxic therapy group was 15% (n=10) vs. 9% (n=2) in the no genotoxic therapy group (p =0.33). Two subjects developed a hematologic malignancy (one case each of CLL and CML); both had prior chemotherapy and radiation exposure (Table). Conclusions: Cancer survivors with a germline PALB2 pathogenic variant and subsequent exposure to genotoxic therapy appear to have low risk of secondary hematologic malignancy. Although two subjects in the chemotherapy group developed leukemias, given the cases seen it is unlikely that these relate to the treatment exposure. Given the small sample size and retrospective nature of this study, more investigation is necessary to fully quantify the risk of therapy-related myeloid neoplasm in patients with germline PALB2 pathogenic variants. [Table: see text]

Impact of molecular therapy on radioactive iodine uptake in patients with oncogene-driven metastatic differentiated thyroid cancer.

TPS10078 Background: Targetable kinase fusions and mutations are common in pediatric and young adult patients with papillary thyroid cancer (TC) and are associated with metastatic disease and lack of response to radioactive iodine therapy (RAI). While survival outcomes are excellent, less than 20% of children with metastatic TC achieve a complete response to standard treatment with surgery and radioactive iodine (RAI). Thus, repeated RAI therapy is common, increasing the risk of pulmonary fibrosis and secondary malignancies. Targeted kinase inhibitors are highly effective at shrinking oncogene-driven TC. Preliminary data suggest that these targeted therapies can improve tumor differentiation and RAI sensitivity. However, optimal integration of targeted therapy with standard of care RAI for TC remains uncertain. The objective of this study is to evaluate if targeted inhibitors in patients with metastatic, oncogene-driven differentiated TC will improve or restore tumor RAI uptake and ultimately induce durable clinical responses in patients with metastatic differentiated TC. Methods: Patients with TC lung metastases, both RAI naïve and refractory, with an identified targetable molecular driver (Table) and intent to start oncogene-specific targeted therapy are eligible for this study. Patients who received a prior oncogene-specific targeted therapy are excluded. A RAI-whole body scan (WBS) is performed at baseline and after 4 weeks of targeted therapy. Patients will be followed for up to 5 years to monitor clinical response. Response parameters include structural (CT, WBS, and/or neck US) and biochemical (thyroglobulin, thyroglobulin antibodies) evaluation. The primary endpoint is the change in RAI avidity between baseline and 4 weeks of treatment. This will be calculated as the ratio of RAI uptake in the lungs/disease sites versus the whole body for each subject at each time point. Secondary endpoints include progression free survival and the proportion of patients who achieve a complete response to the combination of targeted therapy and RAI. Five of 32 patients have been enrolled. Clinical trial information: NCT05024929 . [Table: see text]