Molecular and Clinical Profile of a RET-Rearranged Colorectal Cancer With Prolonged Response to Platinum Therapy and Subsequent Targeted Treatment With Selpercatinib

Introduction

The introduction of next-generation sequencing (NGS) into routine oncology has enabled the identification of actionable genomic alterations across multiple solid tumors.¹ In colorectal cancer (CRC), the most frequent alterations involve RAS, BRAF, and PIK3CA mutations.² Gene fusions, by contrast, are rare (<1%), but may define unique molecular subsets with potential therapeutic relevance.³ Rearranged during transfection (RET) gene fusions, while well-characterized in thyroid and lung cancers, remain poorly understood in CRC.

RET encodes a receptor tyrosine kinase that activates downstream MAPK, PI3K/AKT, and JNK signaling pathways, contributing to oncogenesis when aberrantly activated.^4,5 Selective RET inhibitors, including selpercatinib and pralsetinib, have shown efficacy in RET-driven non–small cell lung cancer and thyroid cancer, and emerging data suggest potential activity across other RET fusion–positive solid tumors.^6-8 Here, we describe a case of a patient with metastatic CRC (mCRC) harboring a RET-NCOA4 fusion and a RAD50 mutation. The patient achieved a durable response to first-line platinum-based chemotherapy, followed by disease control with selpercatinib and subsequent surgical resection of a resistant hepatic metastasis. This case illustrates the relevance of comprehensive genomic profiling (CGP) in CRC and highlights potential therapeutic and biological implications of RET fusions and RAD50 mutations.

Methods

Patient Consent

The authors have obtained written consent from the patient to publish the details in this study. This study was written in compliance with the 1975 Declaration of Helsinki.

Next-Generation Sequencing

Targeted NGS was performed as part of the FPG500 clinical trial (ClinicalTrials.gov identifier: {L-End} NCT06020625), currently ongoing at our institution. As previously described in one of our studies,⁹ tumor samples were subjected to CGP using the TruSight Oncology 500 High Throughput assay (TSO500HT, Illumina Inc, San Diego, CA). This internally validated assay detects single-nucleotide variants (SNVs) and insertions/deletions in 523 genes, copy number variations (CNVs) in 59 genes, and gene fusions and splice variants in 55 genes at the RNA level. It also provides estimates of tumor mutational burden (TMB) and microsatellite instability status. The panel can reliably detect exon or splice site variants with a variant allele frequency (VAF) of >5%. For the interpretation of the identified alterations, we adhered to the guidelines for the interpretation and reporting of sequence variants in cancer jointly issued by the Association for Molecular Pathology, ASCO, and the College of American Pathologists.¹⁰

Case Presentation

A 54-year-old woman presented to the emergency unit with anemia and abdominal pain. A contrast-enhanced (CE) computed tomography (CT) scan revealed a cecal mass with lymphadenopathy and multiple liver metastases. Being symptomatic, she was subjected to right hemicolectomy with lymphadenectomy, and pathology demonstrated a poorly differentiated adenocarcinoma with 11 of 22 lymph nodes involved (pT3pN2b). The tumor showed a cribriform growth pattern. Mismatch repair protein status was proficient (pMMR), and polymerase chain reaction–based molecular profiling revealed wild-type KRAS, NRAS, and BRAF.

Despite the young age and the need for tumor shrinkage, because of the high tumor burden, the patient was unfit for intensified chemotherapy with triplet regimen as the Eastern Cooperative Oncology Group performance status was 2, so first-line modified infusional fluorouracil (5-FU), leucovorin, and oxaliplatin (FOLFOX) plus bevacizumab was started. A rapid decline in circulating tumor marker levels was observed (Fig 1), and tumor assessment with seriate CE-CT imaging showed a major radiologic response, with marked and progressive reduction of hepatic tumor burden (Fig 2) up to persistence of a single remnant metastasis within segment VIII. Maintenance 5-FU/leucovorin plus bevacizumab was initiated and administered for 49 cycles. Meanwhile, the case underwent repeated multidisciplinary evaluations by the institutional Hepatobiliary Tumor Board. Surgical resection was considered unfeasible because of the high number of vanishing metastases. Liver transplantation was ruled out because of suspected extrahepatic disease: specifically, intraoperative findings from the previous surgery suggested possible peritoneal involvement of the right lateral conal fascia although no biopsy and histopathologic confirmation was performed at that time.

FIG 1.

Trend of tumor markers (CEA and Ca 19.9) over the course of the patient's clinical history. CEA, carcinoembryonic antigen.

FIG 2.

Timeline of the presented case. Imaging studies are included to provide a more detailed characterization of the patient's disease burden throughout the clinical course. FOLFIRI, fluorouracil, leucovorin, and irinotecan; FOLFOX, infusional fluorouracil, leucovorin, and oxaliplatin; LFA, leucovorin; PD, progression of disease; PR, partial response.

After more than 2 years since the first-line start, progression of the residual hepatic metastasis prompted reintroduction of FOLFOX plus bevacizumab and stereotactic radiotherapy, but the lesion further progressed. A second-line regimen with 5-FU, leucovorin, and irinotecan plus bevacizumab was attempted, but disease progressed after seven cycles. Rechallenge with FOLFOX was attempted but discontinued because of infusion reactions. Concurrently, CGP with TSO500Illumina on the archival tumor tissue sample was performed aiming to rule out possible factors of primary resistance to anti-EGFRs. CGP confirmed the RAS and BRAF wild-type status and identified a RET-NCOA4 fusion (Fig 3; breakpoints: chr10:51586409 NCOA4, exon 10; chr10:43612030 RET, intron 11, with an in-frame consequence COSF1501; fusion supporting reads: 97). Moreover, the analysis reported a RAD50 SNV (p.R1152*, c.3454C>T, VAF [%]: 17.8) and multiple CNVs (CCND1, ERBB2, CCND1, MET, MYC, RICTOR, FGF3, FGF4, FGF19); microsatellite status was stable, and TMB was low (4 muts/Mb). Complete data are shown in Figure 4.

FIG 3.

The image schematically illustrates the location of the RET and NCOA4 genes on chromosome 10, their respective domains, and the structure of the resulting RET-NCOA4 fusion gene. The fusion retains the IC portion of RET, which possesses kinase activity and becomes constitutively activated, leading to enhanced downstream signaling. IC, intracellular; RET, rearranged during transfection.

FIG 4.

Bubble plot showing the mutations detected in the tissue sample of the primary colon tumor and in the resected liver metastasis sample after selective pressure from selpercatinib. On the right, a legend clarifies the type of molecular alteration identified in each gene and the corresponding VAF in the case of SNVs or the copy number in the case of CNVs. CNV, copy number variation; SNV, single-nucleotide variant; VAF, variant allele frequency.

Based on this actionable alteration, the Molecular Tumor Board advised targeted therapy with the RET-selective inhibitor selpercatinib. Treatment was started within a compassionate use program. Selpercatinib was well-tolerated as patient reported mild G1 adverse events (including loss of appetite, fatigue, diarrhea, stomatitis, and dry skin) and no dose reduction was necessary. The carcinoembryonic antigen (CEA) serum level dropped from 114 to 4.4 ng/dL, and CE-CT scan after 3 months showed a partial response. However, the following CT scan revealed an increase in viable tissue tumor at the periphery of the necrotic lesion in segment VIII; despite no evidence of peritoneal metastases, a scarce perihepatic fluid and right pleural effusion was observed. Accordingly, a slight increase in CEA serum level was observed (up to 22 ng/dL). The following liver magnetic resonance imaging and fluorodeoxyglucose positron emission tomography scan excluded other metastases. Given the limited disease burden, multidisciplinary assessment within the institutional Hepatobiliary Tumor Board was repeated. Taking into account the sustained clinical complete response with the exception of the single residual metastasis in segment VIII, this time the board recommended surgical resection of the oligoprogressive lesion. After 7 months, selpercatinib was interrupted and the patient underwent surgery. Laparoscopy showed milky peritoneal fluid, whose extemporaneous cytologic analysis was negative (Figs 5A and 5B). There were no signs of peritoneal metastases, and intraoperative ultrasonography confirmed the previously identified lesion in segment 8, which was adherent to the diaphragm and showed a peripheral hypoechoic pattern suggestive of peripheral viable tumor tissue. The procedure was then continued with laparotomy and anatomic resection of hepatic segment 8 with partial extension to segment 7, cholecystectomy, and diaphragmatic resection. Histopathologic analysis confirmed a metastatic adenocarcinoma (with 85% necrosis and 1% fibrosis; tumor regression grade was 3) with clear surgical margins (Fig 6). Microbiological examination of peritoneal fluid was negative; the triglyceride concentration was 9,101 mg/dL, confirming chylous ascites. Postoperative course was uneventful, and ascites fully recovered with a very low-fat diet (with medium-chain triglyceride).

FIG 5.

(A) Intraoperative finding of chylous ascites in the perihepatic region. (B) Macroscopic view of the hepatic specimen removed during liver resection, showing the intraparenchymal neoplastic region.

FIG 6.

Histopathologic images showing (A and B) the colorectal cancer, (C and D) locoregional nodal metastasis removed with the colon cancer, and (E and F) liver metastases. (E and F), the necrotic response to selpercatinib is visible with only a residual rim of neoplastic cells underneath the fibrotic capsule.

CGP on the resected liver metastasis confirmed the RET-NCOA4 fusion. Additional novel genomic alterations were identified, including a c.787+1_788-1del9 splice-site mutation in SMAD4 and amplifications of DNMT3B and IRS—alterations not present in the baseline genomic profile (Fig 4).

To date, after almost a year since the surgery, follow-up CE-CT scans have shown no evidence of disease recurrence and the CEA serum level is negative.

Discussion

RET fusions are extremely rare in CRC, detected in fewer than 1% of cases, but represent actionable oncogenic drivers. RET-NCOA4 is among the most frequent rearrangements, leading to constitutive RET kinase activation. Selective RET inhibitors such as selpercatinib and pralsetinib have demonstrated high efficacy in lung and thyroid cancers, whereas activity in CRC has been modest in clinical trials.^11,12 Nonetheless, this case underscores that clinically meaningful responses can occur and supports routine use of CGP in refractory or atypical CRC.

CGP not only identifies actionable targets but can also predict resistance to anti-EGFR therapy, particularly in right-sided, RAS/BRAF wild-type, pMMR tumors. In this patient, detection of a RET-NCOA4 fusion guided the use of selpercatinib and spared ineffective anti-EGFR therapy.^13,14

The drug induced tumor shrinkage that enabled possible curative surgery of a resistant hepatic lesion. Postselpercatinib CGP revealed new alterations, including SMAD4 loss and gene amplifications, highlighting clonal evolution and mechanisms of acquired resistance.¹⁵ SMAD4 inactivation is associated with tumor aggressiveness and may bypass RET dependency, underscoring the need for longitudinal profiling.¹⁶

Surgery and local treatments remain integral in the CGP era, particularly for oligoprogression.¹⁷ Their integration with systemic therapy can extend disease control, as seen in this case.

Remarkably, CGP also showed a RAD50 mutation. Mutations or functional loss of RAD50 has been associated with increased sensitivity to platinum-based chemotherapy because of the central role of RAD50 in DNA damage repair. RAD50 is a key component of the MRN complex (MRE11–RAD50–NBN), which is responsible for sensing DNA double-strand breaks and initiating repair through homologous recombination (HR).¹⁸ Platinum agents induce DNA crosslinks that can evolve into double-strand breaks during DNA replication, making effective HR essential for cell survival.

When RAD50 function is impaired, the MRN complex becomes less efficient in coordinating DNA damage signaling and repair, leading to an HR-deficient (HRD) phenotype. As a consequence, tumor cells accumulate unrepaired DNA damage after platinum exposure, resulting in cell cycle arrest and apoptosis. This biological vulnerability underlies the observed association between RAD50 deficiency and enhanced platinum sensitivity. While not yet validated in CRC, HRD status represents a predictive biomarker of platinum responsiveness in other solid tumors.¹⁹

Finally, this case documents chylous ascites, a rare adverse event of RET inhibitors.²⁰ Recognizing this toxicity is essential to avoid misdiagnosis of progression.

Overall, CGP optimizes treatment by identifying druggable targets, sparing ineffective options, and informing chemotherapy choice, whereas multidisciplinary strategies combining systemic therapy, surgery, and molecular monitoring remain crucial in mCRC.

AUTHOR CONTRIBUTIONS

Conception and design: Giovanni Trovato, Felice Giuliante, Sergio Alfieri, Maria Alessandra Calegari

Provision of study materials or patients: Maria Alessandra Calegari

Collection and assembly of data: Giovanni Trovato, Michele Basso, Agostino Maria De Rose, Eleonora Nardi, Vincenzo Arena, Giampaolo Tortora, Maria Alessandra Calegari

Data analysis and interpretation: Giovanni Trovato, Angelo Minucci, Lisa Salvatore, Giampaolo Tortora, Maria Alessandra Calegari

Manuscript writing: All authors

Final approval of manuscript: All authors

Accountable for all aspects of the work: All authors

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to {L-End} www.asco.org/rwc or {L-End} ascopubs.org/po/author-center.

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