Target Heterogeneity in Oncology: The Best Predictor for Differential Response to Radioligand Therapy in Neuroendocrine Tumors and Prostate Cancer

Abstract

Tumor or target heterogeneity (TH) implies presence of variable cellular populations having different genomic characteristics within the same tumor, or in different tumor sites of the same patient. The challenge is to identify this heterogeneity, as it has emerged as the most common cause of ‘treatment resistance’, to current therapeutic agents. We have focused our discussion on ‘Prostate Cancer’ and ‘Neuroendocrine Tumors’, and looked at the established methods for demonstrating heterogeneity, each with its advantages and drawbacks. Also, the available theranostic radiotracers targeting PSMA and somatostatin receptors combined with targeted systemic agents, have been described. Lu-177 labeled PSMA and DOTATATE are the ‘standard of care’ radionuclide therapeutic tracers for management of progressive treatment-resistant prostate cancer and NET. These approved therapies have shown reasonable benefit in treatment outcome, with improvement in quality of life parameters. Various biomarkers and predictors of response to radionuclide therapies targeting TH which are currently available and those which can be explored have been elaborated in details. Imaging-based features using artificial intelligence (AI) need to be developed to further predict the presence of TH. Also, novel theranostic tools binding to newer targets on surface of cancer cell should be explored to overcome the treatment resistance to current treatment regimens.

Predictive and prognostic potential of pretreatment 68Ga-PSMA PET tumor heterogeneity index in patients with metastatic castration-resistant prostate cancer treated with 177Lu-PSMA

“…Pre-treatment diagnostic 68Ga-PSMA PET-CT is traditionally used for patient selection for 177Lu-PSMA therapy; however, in most studies, response to therapy cannot be predicted with quantitative PET factors such as SUV max ( 25 – 27 ). Nowadays, computerized diagnostics of RFs are used for the prediction of different treatment agents in several cancers ( 28 , 29 ). The present study was conducted to predict response to 177Lu-PSMA therapy and also survival in mCRPC patients using clinical parameters and RFs extracted from pre-treatment 68Ga-PSMA PET-CT images.…”

“…Second, it allows for a longitudinal study. Finally, imaging makes it possible to assess heterogeneity between patients with similar tumors (interpatient heterogeneity), between different tumors within each patient (intertumor heterogeneity), and within the tissue itself (intratumor heterogeneity) ( 28 ). According to the results of the present, patients with higher entropy resulting in more heterogenous lesions were more responsive to 177Lu-PSMA therapy.…”

Neuroendocrine Tumors and Peptide Receptor Radionuclide Therapy: When Is the Right Time?

“…36,37 SSTR-negative lesions will not respond and are associated with primary treatment resistance because of the absence of the target. 38 An alternative to pretreatment cutoffs is to use posttreatment imaging to evaluate response during therapy. In addition to emitting an electron, 177Lu emits gamma photons that can be imaged using a singlephoton emission computed tomography camera.…”

“…36,37 SSTR-negative lesions will not respond and are associated with primary treatment resistance because of the absence of the target. 38…”

Validation of SV2A-Targeted PET Imaging for Noninvasive Assessment of Neuroendocrine Differentiation in Prostate Cancer

“…The FDA-approved 68 Ga-DOTATATE (NETSPOT™) for somatostatin receptor 2 (SSTR2) positive neuroendocrine tumors (NETs) has been long suggested to diagnose PCa patients with NED. However, recent case reports gave mixed results with wide tumor uptake ranges [ 28 , 29 , 30 , 31 ], in addition to observed intra-patient tumor uptake variations [ 30 , 31 , 32 ]. Obviously, noninvasive assessment of NED in PCa and other cancer types is an unmet clinical need.…”