Response to DNA-damaging agents and PARP inhibitors in ATM mutated metastatic colorectal cancer: case series

Introduction

Ataxia telangiectasia mutated (ATM) is a serine/threonine kinase in the homologous recombination (HR) DNA repair pathway, and its mutations are implicated across multiple tumor types (1). In metastatic colorectal cancer (mCRC), ATM mutations occur in approximately 10% of cases and may define a subset with distinct biology and treatment sensitivity, particularly to DNA-damaging agents and poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi) (2). Germline and somatic mutations may differ in prognostic and predictive significance, especially when bi-allelic inactivation or high variant allele frequency (VAF) is present (3). Tumor and liquid next-generation sequencing (NGS) is increasingly performed in patients with metastatic disease, often at diagnosis or upon progression, to identify actionable mutations, guide therapy selection, and determine eligibility for clinical trials. From a larger institutional cohort at Mayo Clinic, we selected four cases with pathogenic ATM mutations, representing both somatic and germline alterations, to explore their clinical trajectories and therapeutic responses (Figure 1). These cases offer insight into the role of ATM mutations in guiding treatment strategies for mCRC, addressing critical gaps in personalized therapy for this challenging disease. We present this article in accordance with the AME Case Series reporting checklist (available at https://cco.amegroups.com/article/view/10.21037/cco-25-101/rc).

Figure 1 Swimmer plot depicting each of the patient’s treatment and response assessments via RECIST v1.1 criteria. RECIST, Response Evaluation Criteria in Solid Tumors; PARP, poly (ADP-ribose) polymerase.

Case presentation

Ethical statement

This case series was conducted under the Mayo Clinic Arizona Institutional Review Board (IRB) approval (IRB 25-001816), in accordance with the Declaration of Helsinki and its subsequent amendments. Patients from Mayo Clinic Arizona with somatic and/or germline ATM mutations were identified through the Mayo Data Explorer, and a retrospective chart review was performed to collect demographic information and clinical data. Written informed consent for publication of this case series and accompanying images was obtained for cases 1 and 3, who were alive at the time of data collection. For cases 2 and 4, who were deceased, consent was exempt per IRB protocol after unsuccessful attempts to contact next of kin. A copy of the written consent is available for review by the editorial office of this journal. All data were handled in accordance with institutional confidentiality and privacy standards.

Case 1

A 41-year-old Hispanic female with oligometastatic colorectal adenocarcinoma was diagnosed in spring 2017. She received 11 cycles of FOLFOX (5-fluorouracil, oxaliplatin, and leucovorin), achieving partial response in the primary tumor, followed by partial colectomy. Imaging was assessed by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 when applicable for all patients described herein. Post-surgery, she was treated with 5-fluorouracil and bevacizumab for 18 months until disease progression. Liquid and tissue NGS identified a germline ATM mutation (L481* with VAF 51%) and a somatic ATM mutation (R2903* with VAF 26%) (Table 1). She was then treated with FOLFIRI (5-fluorouracil, leucovorin, and irinotecan) plus bevacizumab, achieving partial response for 8 months (Figure 2), before transitioning to capecitabine and bevacizumab maintenance, though disease progressed after 4 months. Due to high HER2 amplification, she entered a research study for tucatinib and trastuzumab (NCT05253651), showing significant response until brain metastases required whole-brain radiation. Afterward, she started FOLFOXIRI (5-fluorouracil, leucovorin, oxaliplatin, and irinotecan), achieving partial response, then moved to capecitabine maintenance before further progression. She is now on fam-trastuzumab deruxtecan-nxki, with partial response noted after three cycles. A summary of treatments and outcomes is listed in Table 2.

Figure 2 CT imaging for case 1 following initial progression after partial colectomy with coronal views demonstrating (A) soft tissue attenuation in the left lower quadrant over a 6.3 cm × 3.6 cm area and (B) 2 months after initiating FOLFIRI plus bevacizumab measuring 2.4 cm × 1.7 cm. Yellow circles indicate site of disease. CT, computed tomography; FOLFIRI, 5-fluorouracil, leucovorin, and irinotecan.

Case 2

A 65-year-old male presented in spring 2020 with left lower quadrant pain. Computed tomography (CT) scans showed a 6.3 cm × 4.2 cm sigmoid mass with pulmonary nodules and peritoneal deposits, suggestive of metastatic disease. Biopsy confirmed metastatic adenocarcinoma from a colon primary. He underwent laparoscopy with loop sigmoid colostomy and peritoneal nodule excision. After 5 months on FOLFOX plus cetuximab, CT scans showed partial response (Figure 3). Six months in, he transitioned to maintenance therapy with cetuximab and 5-fluorouracil. Liquid NGS revealed a somatic ATM mutation (V1268fs with VAF 46%) (Table 1). Three months later following disease progression, he entered a clinical trial of FOLFONI (liposomal irinotecan, 5-fluorouracil, and leucovorin) plus rucaparib (NCT03337087), completing 11 cycles over 10 months with stable disease. There were no grade 4 adverse events by Common Terminology Criteria for Adverse Events (CTCAE) v4.0 guidelines. The only grade 3 adverse events were neutropenia and fatigue. Despite stable imaging, carcinoembryonic antigen (CEA) levels rose (from 24 to 190 ng/dL). He received third- and fourth-line treatments, including trifluridine/tipiracil, before enrolling in hospice, passing away 38 months post-diagnosis. Relevant treatments and outcomes are summarized in Table 2.

Figure 3 CT imaging for case 2 with axial views demonstrating (A) long segment soft tissue thickening and mass like appearance of the distal sigmoid colon and (B) 5 months after initiating FOLFOX showing decreased size of the sigmoid mass and segmental soft tissue thickening. Yellow circles indicate site of disease. CT, computed tomography; FOLFOX, 5-fluorouracil, oxaliplatin, and leucovorin.

Case 3

A 66-year-old man presented in fall of 2020 with metastatic colorectal adenocarcinoma. Liquid NGS was performed (Table 1) and was notable for several somatic mutations in the ATM gene with high VAF involvement, including confirmed germline alteration (Y1556* with VAF 81%). The patient was enrolled in a clinical trial of FOLFONI plus rucaparib as first-line treatment (NCT03337087). After completing 16 cycles over 9 months, there was a dramatic decrease in tumor burden as identified by surveillance positron emission tomography (PET) scan (Figure 4). There was one grade 4 adverse event with febrile neutropenia based on CTCAE v4.0 guidelines, otherwise no other grade 3 events. He was transitioned to maintenance therapy with single-agent rucaparib and sustained partial response for another 19 months (28 months total) before developing progressive disease. Second-line treatment was started with FOLFOXIRI plus bevacizumab, achieving partial response after 6 months of therapy. He was placed on maintenance therapy with capecitabine and bevacizumab for another 7 months before enrolling in a clinical trial with KRAS G12D inhibitor with sustained disease control to date. A summary of the relevant treatments and clinical outcomes is listed in Table 2.

Figure 4 PET-CT imaging for case 3 with coronal views demonstrating (A) hypermetabolic right lower quadrant peritoneal/mesenteric mass plus focal hypermetabolism in the distal duodenum/proximal jejunum with marked associated bowel wall thickening and (B) 9 months after initiating FOLFIRI + rucaparib showing a dramatic decrease in metabolic activity at both large previously identified malignant sites involving the duodenal jejunal junction and the right lower quadrant. Yellow circles indicate site of disease. CT, computed tomography; FOLFIRI, 5-fluorouracil, leucovorin, and irinotecan; PET, positron emission tomography.

Case 4

A 50-year-old African American male presented in spring 2019 with a 6.6 cm hepatic flexure mass found on colonoscopy, confirmed as colon adenocarcinoma, along with a 3.3 cm nodal metastasis and numerous hepatic metastases. Liquid NGS identified a separate pathogenic somatic ATM mutation (c.6006+2T>C with VAF 36%) (Table 1). He received FOLFOXIRI plus bevacizumab for 4 months, achieving partial response in the primary tumor and hepatic metastases (Figure 5). He then switched to maintenance capecitabine and bevacizumab for 5 months before progression. After a right hemicolectomy, he began FOLFIRI plus bevacizumab, with a reduction in all hepatic metastases after 4 months, the largest shrinking from 4.3 to 3.0 cm. He progressed on capecitabine and bevacizumab after 1 month and resumed FOLFOXIRI plus bevacizumab for 6 months, again showing partial response. He was then enrolled in a clinical trial with fruquintinib, but shortly after passed away, 25 months post-diagnosis. Treatments and outcomes are summarized in Table 2.

Figure 5 CT imaging for case 4 demonstrating (A) 6.6 cm circumferential mass at the hepatic flexure of the colon with an adjacent enlarged centrally necrotic 3.3 cm lymph node in the right ileocolic mesentery and (B) 4 months after initiating FOLFOXIRI plus bevacizumab showing decreased size of the hepatic flexure mass now 3.8 cm and decreased size of the mesenteric lymph node 2.6 cm. Surveillance scans 2 months after hemicolectomy showing (C) multiple hepatic metastases and (D) 4 months after initiating FOLFIRI plus bevacizumab showing interval decrease and partial response in the liver lesions. Yellow circles indicate site of disease. CT, computed tomography; FOLFIRI, 5-fluorouracil, leucovorin, and irinotecan; FOLFOXIRI, 5-fluorouracil, leucovorin, oxaliplatin, and irinotecan.

Discussion

ATM mutations in colorectal cancer (CRC)

In the past decade, there have been substantial advances in the utilization of targeted therapies in mCRC (4). With the rise of genetic sequencing, numerous actionable mutations have been identified with increasing interest in targeting DNA repair genes (5,6). One such gene is the ATM gene, which is involved in both HR and non-homologous end-joining DNA repair (1). Prognostically, loss-of-function ATM mutations in mCRC displayed significantly longer median overall survival (OS) when compared to ATM wild-type cancers (64.9 vs. 34.8 months) (2). This prognostic impact was independent from TP53 gene status and primary tumor location. Furthermore, a high VAF (>50%), seen in germline ATM mutations, conferred an OS benefit compared to low VAF (≤50%) (70.1 vs. 38.5 months).

There is growing clinical evidence to suggest HR deficient malignancies, including ATM mutations, are sensitive to therapies that induce DNA double-stranded breaks, such as platinum and topoisomerase inhibitors (7,8). Individually, HR mutations and chemotherapy-induced DNA breaks are non-lethal, but their combination results in “synthetic lethality” (9). Tolerability limits prolonged oxaliplatin/irinotecan use, and fluoropyrimidine maintenance appears equivalent to continued induction in unselected mCRC (10,11). Whether ATM-mutated patients derive a unique benefit is unknown.

The use of PARPi has also been shown to be effective in patients with HR mutated malignancies (12). PARP primarily functions to repair single-stranded breaks via base excision repair (BER) but also has the capacity to repair double-stranded breaks (13). In BRCA-mutated ovarian cancer, PARPi significantly prolongs progression-free survival (PFS) (14). In mCRC, phase II trials combining PARPi with chemotherapy have resulted in significant toxicity issues with unclear clinical benefit to date (15-17). These studies did not stratify patients by HR status, though preclinical models suggest HR-deficient CRC may be responsive, particularly when combined with DNA-damaging agents (18,19).

Another important consideration in HR mutated cancers is the concept of loss of heterozygosity (LOH). This type of genetic alteration occurs when one allele is lost at a particular locus through various mechanisms, including deletion, mitotic non-disjunction, or somatic recombination (20). The prevalence of LOH in the HR pathway occurs in 10–16% of patients and also varies depending on the level of microsatellite instability (21). The lack of response in previously published studies of PARPi in CRC suggests that patients with underlying HR mutations may not have concurrent LOH.

In the case of ATM mutations in CRC, a second genetic event is often required to fully inactivate the tumor-suppressing functions of the ATM protein (3). Due to its large size, the ATM gene is prone to accumulating passenger mutations during cancer progression. A sporadic mutation or LOH is essential for complete loss-of-function. Without this secondary event, cancers with ATM mutations may still retain some DNA repair ability, potentially affecting treatment outcomes (3). Understanding this relationship between ATM mutation and LOH is key to explaining variations in responses to DNA-damaging therapies like platinum agents and PARPi.

Response to DNA-damaging agents

The case series highlights notable clinical outcomes in patients with mCRC treated with DNA-damaging regimens, emphasizing the interplay between ATM mutations, HR deficiency, and therapeutic response. All four patients achieved a partial response during their disease course, with a median PFS of 18.5 months and OS of 47.5 months, exceeding historical benchmarks for similar mCRC populations treated with doublet chemotherapy (22,23).

Among the four cases, patients 1 and 3 had confirmed germline ATM mutations (L481* and Y1556*, respectively) with high VAFs (>50%), while patient 2 had a suspected germline ATM mutation due to a VAF of 46.4%. Although never confirmed with NGS, prior studies suggest germline origin when allele frequency is approximately 50% (24). High VAFs suggest a significant disruption in HR repair mechanisms, potentially enhancing sensitivity to DNA-damaging agents, such as platinum-based chemotherapy, through synthetic lethality.

Patient 4, in contrast, harbored non-truncating ATM mutations (c.6006+2T>C and G3030E), which may have retained partial ATM function. The clinical significance of the G3030E missense variant remains uncertain, as functional validation is limited and current databases such as ClinVar classify it as a variant of uncertain significance (VUS). Despite this, the observed response was significant and may have been driven by additional somatic co-mutations such as PTEN, contributing to the overall genomic instability. Previous studies support this, showing that PTEN-deficient cancers exhibit increased levels of DNA damage markers like γ-H2AX when treated with platinum-based agents (25). The combined effect of these alterations may mimic the HR-deficient phenotype seen in truncating mutations, highlighting a broader spectrum of ATM-related vulnerabilities to DNA-damaging agents.

Although LOH was not directly assessed in our cohort, its potential impact on predicting responses to DNA-damaging agents remains significant. Both patients 1 and 3 had germline mutations paired with one or more somatic alterations in the ATM gene, contributing to biallelic inactivation. The unusually high VAF (81%) of the germline ATM Y1556 mutation in patient 3 may reflect LOH or amplification of the mutant allele and contributing to the observed therapeutic response. These profiles illustrate the double-hit model of HR deficiency, where biallelic gene inactivation drives genomic instability and potential sensitivity to platinum agents or PARPi.

While oxaliplatin and irinotecan have both been shown to induce DNA double-strand breaks, their interactions with HR deficiency differ mechanistically. Oxaliplatin forms DNA crosslinks that are preferentially repaired through nucleotide excision repair and HR, while irinotecan inhibits topoisomerase I, creating replication-associated single-strand breaks that are converted to double-strand breaks during replication stress (26,27). HR-deficient cells may therefore exhibit differential sensitivity to these agents, which could partly explain interpatient variability in treatment responses.

A key limitation of our analysis is the absence of direct LOH assessment for the ATM gene. Although high VAFs and secondary mutations suggest possible biallelic inactivation, these are indirect indicators and cannot confirm LOH without orthogonal testing [e.g., single-nucleotide polymorphism (SNP) arrays]. This limits certainty in linking ATM loss to therapeutic response. Accurate classification of ATM variants remains essential, as non-truncating alterations such as splice site variants may also impair function. For instance, patient 4 carried a canonical splice site mutation (c.6006+2T>C), predicted to disrupt splicing and classified as likely pathogenic in ClinVar (28). Future studies should incorporate comprehensive profiling, including LOH analysis, to better define HR-deficient subsets and inform treatment selection.

Response to PARPi

Several of the patients described in the case series were also treated with PARPi during their disease course. Inhibition of these mechanisms is thought to be particularly effective in malignancies containing mutations to HR repair, such as BRCA or ATM mutations (29). The response profiles of patients in our case series who were treated with PARPi in addition to DNA-damaging regimens were more variable (Table 2). However, one of the patients (patient 3) sustained a durable partial response of over 28 months in the first-line setting. PFS of patients treated with combination rucaparib plus FOLFONI varied between 6 and 28 months and OS between 38 and 42 months. Treatment with PARPi was administered in first and second line settings, which accounted for the discrepancy in outcomes.

PARPi were also given in combination with chemotherapy, making it difficult to isolate their independent effect. Durable responses may reflect chemotherapy activity or potential synergy rather than PARPi alone. Moreover, the presence of co-mutations, such as PTEN loss observed in patient 4, may modulate treatment response in ways that are not yet fully understood, potentially interacting with HR repair deficiencies to influence sensitivity or resistance to therapy. Nonetheless, these results are encouraging when considering the historic outcomes of similar patient populations (30). The benefit of PARPi in HR deficient CRC is yet to be determined, and ongoing research is focused on identifying combination therapies that may sensitize tumors to PARPi and overcome resistance mechanisms. Although only two patients in this series received PARPi, both demonstrated disease control beyond expected durations. These findings are exploratory and should be interpreted cautiously, serving as preliminary evidence that supports continued evaluation of PARP inhibition in biomarker-defined subsets of CRC. The role of PARPi in combination therapy is under active investigation. PARPi plus immune checkpoint inhibitors are being tested in mismatch repair-proficient CRC, pancreatic adenocarcinoma, and leiomyosarcoma (NCT03851614). Despite a phase I study with olaparib plus irinotecan showing minimal benefit in patients with advanced CRC, clinical data regarding outcomes with PARPi is lacking (31). Moreover, preclinical models have shown ATM-mutated CRC cell lines are sensitive to PARPi with olaparib and may impose synergy when combined with DNA-damaging agents such as irinotecan (18,19). Furthermore, post-treatment maintenance with PARPi in mice models enriched with KRAS and BRAF mutations with concurrent HR mutations showed delayed disease progression in mice (32). In this regard, there is an ongoing phase I clinical trial to evaluate a novel sequential dosing of rucaparib with FOLFONI in metastatic gastrointestinal (GI) cancers (NCT03337087) (33). Given the improved outcomes in other HR deficient malignancies as well as preclinical models demonstrating sensitivity to PARPi, this unique treatment modality may be a promising addition to the options available for such patients in the future.

Conclusions

This case report describes four patients with mCRC harboring ATM mutations, with confirmed germline involvement in two of the cases. All patients achieved at least a partial response, with significant reductions in CEA levels following DNA-damaging agents, with or without PARPi. The most substantial response occurred in a patient with a germline ATM mutation treated with PARPi and chemotherapy in the first-line setting. All patients in the cohort met or exceeded historical expectations of those with mCRC, with the most favorable response occurring in those with double-hit or germline involvement. These cases highlight the importance of NGS in guiding targeted therapies for ATM mutated mCRC, particularly with drugs like platinum agents, topoisomerase inhibitors, and PARPi. Though the small sample size and potential biases of this case series require cautious interpretation, further exploration of PARPi and other DNA repair-targeting agents as first-line or maintenance therapy is warranted.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the AME Case Series reporting checklist. Available at https://cco.amegroups.com/article/view/10.21037/cco-25-101/rc

Peer Review File: Available at https://cco.amegroups.com/article/view/10.21037/cco-25-101/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://cco.amegroups.com/article/view/10.21037/cco-25-101/coif). T.B.S. serves as an unpaid editorial board member of Chinese Clinical Oncology from April 2024 to March 2026. And he has the following disclosures: research funding (to institution): Agios, Arys, Arcus, Atreca, Boston Biomedical, Bayer, Eisai, Celgene, Lilly, Ipsen, Clovis, Seattle Genetics, Genentech, Novartis, Mirati, Merus, Abgenomics, Incyte, Pfizer, and BMS; consulting (to institution): Servier, Ipsen, Arcus, Pfizer, Seattle Genetics, Bayer, Genentech, Incyte, Eisai, Merus, Merck KGaA, and Merck; consulting (to self): Stemline, AbbVie, Blueprint Medicines, Boehringer Ingelheim, Janssen, Daiichi Sankyo, Natera, TreosBio, Celularity, Caladrius Biosciences, Exact Science, Sobi, Beigene, Kanaph, Astra Zeneca, Deciphera, Zai Labs, Exelixis, MJH Life Sciences, Aptitude Health, Illumina, Foundation Medicine and Sanofi, Glaxo SmithKline, and Xilio; IDMC/DSMB: The Valley Hospital, Fibrogen, Suzhou Kintor, Astra Zeneca, Exelixis, Merck/Eisai, PanCan, and 1Globe; scientific advisory board: Imugene, Immuneering, Xilis, Replimune, Artiva, and Sun Biopharma; royalties: UpToDate; inventions/patents: WO/2018/183488: Human PD1 Peptide Vaccines and Uses Thereof—licensed to Imugene, WO/2019/055687: Methods and Compositions for the Treatment of Cancer Cachexia—licensed to Recursion. M.B.S. has the following disclosures: Novartis (consulting fees to self); Boehringer Ingelheim and Bayer (consulting fees to institution); Taiho and Eli Lilly (research support to institution). C.W. reports advisory board roles to the following: Seagen, Exelixis, Pfizer, Merck, Natera, and DoMore Diagnostics. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. This case series was conducted under the Mayo Clinic Arizona Institutional Review Board (IRB) approval (IRB 25-001816), in accordance with the Declaration of Helsinki and its subsequent amendments. Written informed consent for publication of this case series and accompanying images was obtained for cases 1 and 3, who were alive at the time of data collection. For cases 2 and 4, who were deceased, consent was exempt per IRB protocol after unsuccessful attempts to contact next of kin. A copy of the written consent is available for review by the editorial office of this journal.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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