Homologous Recombination Repair Defect May Predict Treatment Response to Peptide Receptor Radionuclide Therapy for Neuroendocrine Tumors

Abstract

Lutetium‐177‐dotatate (¹⁷⁷Lu‐dotatate), a form of peptide receptor radionuclide therapy, was approved by the U.S. Food and Drug Administration for the treatment of advanced somatostatin receptor–positive gastroenteropancreatic neuroendocrine tumors (NETs) in 2018 based on the promising results of the NETTER‐1 trial for grade 1–2 midgut NETs. Here, we present a patient with a grade 3 pancreatic neuroendocrine tumor and BRCA1 germline mutation who had a significant response to ¹⁷⁷Lu‐dotatate.

Short abstract

This article describes a patient with high‐grade pancreatic neuroendocrine tumor and BRCA1 germline mutation who had a significant response to Lutetium‐177‐Dotatate and summarizes the current state of clinical management of high‐grade neuroendocrine tumors.

Introduction

Pancreatic neuroendocrine tumors (PNETs) make up 1%–2% of pancreatic cancers in the U.S. by incidence [1]. They are divided into well‐differentiated neuroendocrine tumors (NETs) and poorly differentiated neuroendocrine carcinomas (NECs); well‐differentiated NETs are further stratified into three groups (grade [G]1, G2, and G3) based on Ki67 index and mitotic count, which are prognostic [2]. Survival for patients with NETs has been improving; however, the prognosis of G3 PNETs remains poor with a median overall survival of 29–99 months [3]. Other than surgical resection, there is a lack of data to guide treatment of G3 PNETs.

Patient Story

A 68‐year‐old man with type 2 diabetes mellitus on metformin initially presented to the orthopedics clinic in a tertiary medical center for a second opinion on left hip and back pain that were aggravated by activities. Review of system was also positive for fatigue and weight gain. On physical examination, he appeared healthy with an abnormal gait and reduced stance phase on the left side. Neurovascular examination was otherwise normal. Given abnormal signals in the left acetabulum and right posterior ilium on magnetic resonance imaging, he underwent a nuclear bone scan and computed tomography (CT) of the chest, abdomen, and pelvis for concerns of metastatic disease. These revealed a 4.7‐cm irregularly shaped and hypoenhancing mass in the pancreatic tail with evidence of innumerable ill‐defined masses in the liver and multiple sclerotic bony lesions. A liver biopsy showed a metastatic, well‐differentiated, G3 NET consistent with a pancreatic primary, Ki67 of 40%, and positive staining for chromogranin, synaptophysin, and Cam 5.2. Subsequent gallium‐68‐dotatate positron emission tomography (PET)/CT showed avid lesions in the tail of the pancreas, liver, and posterior peripancreatic and left retroperitoneal lymph nodes (Fig. 1A).

Figure 1.

Gallium‐68‐dotatate positron emission tomography‐computed tomography scans of the patient: (A) at diagnosis, (B) during and (C) after treatment with lutetium‐177‐dotatate.

The patient started with capecitabine plus temozolomide (CAPTEM) [4] and monthly octreotide acetate and denosumab injections, but unfortunately, repeat PET scan after two cycles of treatment showed mixed response. Therefore, lutetium‐177‐dotatate (¹⁷⁷Lu‐dotatate) was proposed and he received another two cycles of CAPTEM until this could be arranged. Four treatments of ¹⁷⁷Lu‐dotatate were given without complications. Interval PET scan following two treatments showed remarkable improvement (Fig. 1B); repeat scan 3 months after completion of treatment showed continued improvement (Fig. 1C). He also experienced significant pain relief and was able to return to his normal activities.

The patient's family history was significant for BRCA1‐positive ovarian cancer in his mother, sister, and daughter. Therefore, he underwent genetic testing via next‐generation sequencing, which showed a pathogenic, heterozygous BRCA1 germline mutation (c.68_69delAG) based on the Invitae BRCA1 and BRCA2 STAT Panel. This was confirmed by the Tempus Onco‐seq Panel that further revealed somatic mutations in ATRX, BCOR, and FBXW7 and tumor mutational burden of 0.5 mutations/Mb.

Discussion

Classification of G3 PNETs is marked by controversies. Diagnosis and prognosis of this tumor group depend on both cell morphology (degree of differentiation) and rate of cell proliferation (Ki67 and mitotic rate). Owing to overlapping histologic features, G3 NETs are hard to distinguish from NECs [5, 6]. The impact of functional status (capability of hormone production) on survival is also unknown. As a result, there is considerable heterogeneity in clinical outcomes within the World Health Organization G3 category (well‐differentiated PNETs with Ki67 > 20%). Our patient has a well‐differentiated PNET with Ki67 < 55%. The median overall survival for this group of patients was estimated to be 43.6 months [7].

There are no randomized trials to guide systemic treatment of G3 PNETs. For unresectable tumors, the National Comprehensive Cancer Network recommends personalized management based on clinical judgement with consideration of treatment options for G1–2 tumors. Some small‐scale studies support the use of somatostatin analogues alone or in combination with systemic therapies (platinum‐based therapy, peptide receptor radionuclide therapy [PRRT], targeted agents, etc.) [3]. The SWOG S1609 (DART) trial showed preliminary efficacy of nivolumab plus ipilimumab in high‐grade NETs, but the reported analysis did not include patients with PNETs or specified outcomes based on cell morphology (G3 NETs vs. NECs) [8]. Here, we report a patient with a G3 PNET who was successfully treated with PRRT, providing strong evidence for the NETTER‐2 trial, which aims to evaluate the safety and efficacy of ¹⁷⁷Lu‐dotatate in advanced G2–3 gastroenteropancreatic NETs.

Conclusion

Our patient has a germline mutation in BRCA1, a common mutation causing homologous recombination repair defect (HRD) in many types of cancer. Based on the concept of synthetic lethality, tumors harboring HRD are more susceptible to therapeutics targeting DNA synthesis and repair. Therefore, PNETs carrying these mutations are more likely to respond to PRRT that damages tumor cell DNA by ionizing radiation. In other words, HRD status may predict favorable treatment response to PRRT. This is critical because of the lack of actionable mutations and reliable predictive biomarkers in PNETs, which has a distinct genetic landscape with a low mutational burden (0.82 mutations/Mb) [9]. Most PNETs arise sporadically, with a small number of cases associated with familial syndromes. Sporadic PNETs rarely have germline mutations, but a recent study reported germline mutations in MUTYH, CHEK2, and BRCA2, which are all DNA repair genes [9]. The increasing recognition of defective DNA repair in tumorigenesis and the fact that HRD may become a therapeutic target [10] highlight the relevance of HRD in the management of high‐grade PNETs. It will be of clinical significance to have a prospective study to evaluate the role of HRD as a predictor for PRRT.

Disclosures

Thorvadur Halfdanarsson: Ipsen (RF), Ipsen, AAA, Curium, Lexicon (SAB); Daniel Ahn: Exelixis, Genentech, Eisai, Ipsen (SAB), AstraZeneca (RF); Tanios Bekaii‐Saab: Boston Biomedical, Bayer, Amgen, Merck, Celgene, Eli Lilly and Company, Ipsen, Clovis, Seattle Genetics, Array Biopharma, Genentech, Abgenomics, Incyte, Bristol‐Myers Squibb (RF [to institution]), Ipsen, Array Biopharma, Bayer, Genentech, Incyte, Merck (C/A [to institution]), AstraZeneca, Exelixis, Eli Lilly and Company, PanCan, 1Globe (IDMC/DSMB), Imugene, Immuneering, Sun Biopharma (SAB). The other authors indicated no financial relationships.

(C/A) Consulting/advisory relationship; (RF) Research funding; (E) Employment; (ET) Expert testimony; (H) Honoraria received; (OI) Ownership interests; (IDMC/DSMB) Independent data monitoring committee/data safety monitoring board; (IP) Intellectual property rights/inventor/patent holder; (SAB) Scientific advisory board