Rare POLE P286R-Mutated Lung Cancer Shows Dramatic Response to Immunotherapy

In the world of lung cancer, few diagnoses are as rare or as poorly understood as hepatoid adenocarcinoma of the lung, a malignancy so uncommon that it accounts for less than 0.1 percent of all lung adenocarcinomas. First described in 1990, this tumor is a biological impostor: although it arises in the lung, it looks and behaves remarkably like hepatocellular carcinoma, the primary cancer of the liver. Now, a case report published in the journal Cancer Reports describes an extraordinary clinical story involving one such tumor, in which a specific mutation in a DNA-repair enzyme appears to have transformed an aggressive, chemotherapy-resistant cancer into one exquisitely vulnerable to immunotherapy. The case offers a striking illustration of how the molecular anatomy of a tumor, rather than its tissue of origin, can determine which treatments will work.

The patient at the center of the report was a 61-year-old man with a history of bullous pulmonary emphysema who underwent a routine chest computed tomography scan in June 2020. The scan revealed a small mass, measuring 15 by 19 millimeters, in the upper segments of his left lung, along with a second smaller lesion in the right lung. Over the following months the left-sided mass grew steadily, and by November 2021 it had invaded the anterior chest wall and the soft tissues of the neck, destroying the first rib. An ultrasound-guided biopsy of the lesion yielded a diagnosis of metastasis from a poorly differentiated adenocarcinoma, thought at the time to originate from a hepatocellular carcinoma.

What followed was a grim demonstration of the tumor’s chemoresistance. The patient received successive lines of chemotherapy—cisplatin with docetaxel, then irinotecan, then gemcitabine, then cisplatin with etoposide—and every regimen failed, with the primary lesion expanding relentlessly from 22 by 23 millimeters to 112 by 64 millimeters over the course of treatment. A palliative course of external beam radiotherapy delivered to the primary tumor and to involved lymph nodes in the left supraclavicular region produced only a modest 29 percent shrinkage. By the time the patient was reassessed, the tumor had become a Pancoast-type cancer of the lung apex, encasing the left subclavian and vertebral arteries and eroding the first rib and adjacent vertebrae.

A careful re-examination of the biopsy material, however, changed the trajectory of the case. Pathologists identified epithelioid cells arranged in nested clusters, expressing cytokeratins 7 and 19 and the hepatocellular marker HepPar-1, while lacking p63, TTF-1, and CDX2—an immunophenotype characteristic of hepatoid adenocarcinoma. Two findings stood out. First, the tumor had lost expression of PMS2, one of the four essential proteins of the DNA mismatch repair system, while retaining MSH6. Second, the tumor cells expressed PD-L1, the molecular target of checkpoint-inhibiting drugs, with a combined positive score of 17. The investigators noted that the specimen was tiny, containing fewer than 100 tumor cells, which placed the PD-L1 assessment at the borderline of reliability, but the overall picture was enough to justify a bold therapeutic decision.

In October 2022, one month after completing radiotherapy, the patient began treatment with pembrolizumab, an antibody that blocks the PD-1 receptor and reinvigorates anti-tumor T cells. The effect was rapid and substantial. After just three infusions, the apical tumor in the left lung had regressed by 45.4 percent, shrinking to 74 by 45 millimeters. Treatment continued, and after 18 cycles the lesion measured 60 by 46 millimeters. More remarkably, a surgical biopsy of a residual supraclavicular lesion performed in November 2023 found only loose connective tissue and foci of necrosis, with no tumor cells whatsoever—a complete morphological response. The right lung lesion, considered a metastasis, diminished by 77.1 percent during therapy, although it was never biopsied, so systemic response is probable but not histologically confirmed.

To understand why the tumor had lost PMS2 and why it might be so immunogenic, the team turned to high-throughput sequencing. Sequencing of the patient’s constitutional DNA from blood leukocytes revealed no pathogenic variants in mismatch repair genes, and MLPA analysis found no deletions or aberrant methylation of MLH1, MSH2, PMS2, or MSH6, effectively excluding Lynch syndrome, the hereditary condition most commonly associated with mismatch repair deficiency. The answer lay in the tumor itself. Panel sequencing of tumor DNA, performed at a median depth of 1515-fold, uncovered biallelic somatic PMS2 mutations—a truncating variant, p.Arg421Ter, and a missense variant, p.Arg107Trp—that together explained the loss of PMS2 protein expression.

But the most consequential discovery was a third variant: POLE p.Pro286Arg, a mutation in the exonuclease domain of DNA polymerase epsilon, the enzyme responsible for proofreading newly synthesized DNA during replication. This substitution, with a variant allele frequency of 13 percent, is a well-known hotspot mutation in endometrial and colorectal cancers, where it disables the polymerase’s proofreading function and unleashes an avalanche of secondary somatic mutations across the genome. In POLE-mutated endometrial carcinomas carrying precisely this substitution, tumor mutational burdens ranging from 78 to 277 mutations per megabase have been reported, with a median of 169; in colorectal cancers with exonuclease domain mutations, burdens averaging 115 mutations per megabase have been documented. Such hypermutated tumors generate abundant neoantigens, making them exceptionally visible to the immune system and highly responsive to checkpoint blockade.

The sequencing also revealed a constellation of additional oncogenic alterations: two TP53 mutations (p.Arg282Trp and p.Arg175Cys), a truncating ARID1B variant, and a PTEN p.Leu320Ser substitution—a mutational profile strikingly similar to that seen in POLE-mutated, so-called multiple-classifier endometrial cancers, where proofreading deficiency secondarily drives inactivation of mismatch repair genes and TP53. The authors propose a coherent mechanistic sequence: the POLE P286R mutation crippled DNA proofreading, the resulting hypermutation disabled PMS2 through biallelic somatic hits, and the accumulated mutational load—combined with PD-L1 expression—rendered the tumor exquisitely sensitive to pembrolizumab. Although the small sequencing panel, spanning only 2.9 kilobases, prevented precise measurement of the tumor mutational burden, the hypermutated phenotype was strongly anticipated from the spectrum of variants found.

The significance of this finding is amplified by the broader genomic context of hepatoid adenocarcinoma of the lung. Only about 191 cases have been described in the literature, and the most comprehensive genomic profiling to date, encompassing 32 sequenced cases, identified 31 recurrently mutated genes including TP53, STK11, SMARCA4, CDKN2A, KRAS, and CDK8. Crucially, reported tumor mutational burdens in this disease have been low, ranging from 1.69 to 8.67 mutations per megabase, and most tumors are microsatellite-stable—features that ordinarily predict poor responsiveness to immunotherapy. Moreover, STK11 inactivation, common in these tumors, is known to create an immunologically cold, T-cell-excluded microenvironment, and the KRAS-STK11 co-mutation is considered among the most immunosuppressive genomic combinations in all of lung cancer. Against this backdrop, a hepatoid adenocarcinoma driven by POLE proofreading deficiency represents an entirely different biological entity, one whose immunogenicity rivals that of the best-responding hypermutated tumors.

The clinical outcome speaks for itself. To the date of last follow-up in June 2026, the patient had received 61 cycles of pembrolizumab—more than three and a half years of continuous disease control—with no adverse events and a good quality of life, a stark contrast to the fulminant progression that characterized his chemotherapy era. The authors suggest that the synergy between radiotherapy and checkpoint inhibition, initiated just one month apart, may have contributed to the response, and they argue that POLE exonuclease domain mutations should be regarded as a tissue-agnostic predictor of high tumor immunogenicity and checkpoint blockade effectiveness. For a tumor type with no standardized treatment algorithm and a historically dismal prognosis, the message of this single case is clear: individual molecular profiling, even in the rarest of cancers, can reveal therapeutic vulnerabilities that no empirical regimen could ever uncover.

Subject of Research: POLE P286R-mutated hepatoid adenocarcinoma of the lung responding to immune checkpoint inhibition

Article Title: A POLE P286R‐Mutated Hepatoid Adenocarcinoma of the Lung Showing Substantial Response to Immune Checkpoint Inhibition

Article References: Chernev, A., Kaurtseva, A., Abasov, R., Enikeev, R., Gegelia, N., Abdrakova, G., Usman, N., Druy, A., & Raskin, G. (2026). A POLE P286R ‐Mutated Hepatoid Adenocarcinoma of the Lung Showing Substantial Response to Immune Checkpoint Inhibition. Cancer Reports, 9(9), Article e70661. https://doi.org/10.1002/cnr2.70661

Image Credits: AI Generated

DOI: 10.1002/cnr2.70661

Keywords: hepatoid adenocarcinoma, lung cancer, POLE P286R, pembrolizumab, mismatch repair deficiency, PMS2 loss, PD-L1, tumor mutational burden, immunotherapy, DNA polymerase epsilon, rare tumors, case report