Efficacy of pembrolizumab in a patient with xeroderma pigmentosum variant and advanced cutaneous squamous-cell carcinoma

Xeroderma pigmentosum (XP) is a rare autosomic recessive disorder of DNA repair pathways that confers photosensitivity along with an increased incidence of ultraviolet (UV)-induced cutaneous cancer [1–3]. Eight XP complementation groups (XP-A to XP-G) and an XP variant (XP-V) related to mutations in different genes involved in DNA repair of UV-induced DNA lesions have been described. We described here a patient with a locally advanced and metastatic cutaneous squamous cell carcinoma (SCC) revealing an XP-V successfully treated with PD-1 antibody, pembrolizumab.

Observation

A 58-year-old man was referred for a locally advanced and metastatic cutaneous SCC. His medical history included an inflammatory bowel disease (IBD) treated by methotrexate, an AJCC 8th stage IA melanoma of the forehead treated by wide excision and a 20-year long history of recurrent cutaneous SCCs of the face treated with multiple iterative surgeries (lower lip, nasofrontal area, scalp, both ears). In 2000, he developed a right cervical mass. Neck dissection revealed an SCC lymph node metastasis with capsular effraction out of 3 lymph nodes, along with an SCC metastasis of the parotid gland. The patient was then lost to follow-up. In May 2021, he presented a recurrence of a right cervical mass surrounding the right mastoid and parotid associated with cervical necrotic lymph nodes (Figure 1). Lymph node SCC metastasis was confirmed by ultrasound-guided biopsy. A total body CT-scan did not show any other suspicious lesions. Methotrexate was discontinued and the patient was treated with pembrolizumab (200 mg every 3 weeks). The patient presented a rapid reduction in tumor mass after the second infusion of pembrolizumab that was still maintained 15 months later (Figure 1) after 19 cycles of pembrolizumab. No flare-up of IBD and other immune-related adverse event were observed. In addition, clinical examination at baseline revealed a skin type II with a striking and severe helioderma (Figure 1), contrasting with a low cumulative UV-exposure reported by the patient. He worked as a watchmaker, did not travel out of France, did not use any tanning beds nor phototherapy nor photosensitizing drugs. Furthermore, knowing his fair skin type and aware of his recurrent skin cancer history, he reported regular sun protection measures. He had one sister and one uncle with similar skin alteration. No familial history of skin cancer was reported. His parents were not consanguineous. A molecular genetic analysis was then performed and demonstrated an homozygotous POLH gene C.225_227 deletion and p.(Leu77Del) mutation leading to the diagnosis of XP-V.

Figure 1. Tumor response of advanced cutaneous squamous cell carcinoma to pembrolizumab with clinical photography (A, B) and cervical MRI images (C-F): Right ulcerative parotid mass, severe helioderma (A) and right surrounding mastoid and parotid mass (C), associated with multiple cervical necrotic lymph nodes (E) before treatment. Major clinical response with complete healing of the skin (B), decrease of the parotid mass (D) and disappearance of several cervical necrotic lymph nodes (F), 3 months after pembrolizumab introduction.

Discussion

XP-V is characterized by a late onset (after 30 years of age) of skin cancers. XP-V patients gradually develop freckling at sun exposed sites and hypo- and/or hyperpigmentation leading to premature skin aging [1–3]. In contrast to XP groups A-G, XP-V cells have normal nucleotide excision repair, but mutations at POLH gene lead to a deficiency in translesion synthesis [3]. As a consequence, UV-induced DNA lesions are replicated by a more error-prone polymerase that produces extra mutations, therefore allowing skin cancers to occur [1–3].

The efficacy of anti-PD1 therapy for the treatment of unresectable advanced SCC in XP patients (Table 1) have been scarcely reported [4–9]. The rapid clinical response to anti-PD1 starting after few infusions may be due to the higher mutational burden in the cutaneous neoplasms because of DNA repair defect. A recent study [10] demonstrated indeed that cumulative sun exposure related to skin location and molecular UV signature were relevant biomarkers directly linked to tumor mutational burden and response to anti-PD1 therapy. In conclusion, our observation confirms the rapid effectiveness of anti-PD1 drugs for the treatment of cutaneous advanced SCC in a patient suffering from XP-V.

Table 1. XP patients with cutaneous neoplasms response to immune checkpoint inhibitor.

Observation	Patient	Treated skin cancer	Immunotherapy	Outcome
Hauschild et al. 2017 [4]	XP-E	Metastatic MM Multiple localized SCCs BCCs AKs	Pembrolizumab	MM: Partial response (C4)
Deinlein et al. 2017 [5]	XP	Metastatic SCC	Pembrolizumab	SCC: Partial response (C3)
Salomon et al. 2018 [6]	XP-C	Metastatic MM Multiple localized SCCs, BCCs and AKs	Pembrolizumab	MM: Partial response (C4)
Steineck et al. 2019 [7]	XP-C	Locally advanced and metastatic SCC	Pembrolizumab	SCC: Partial reponse (C5)
Ameri et al.  2019 [8]	XP-C	Unresectable SCC + BCC	Pembrolizumab	SCC: complete response (C8) BCC: no response
	XP-E	Unresectable SCC	Pembrolizumab	SCC: Partial response
	XP-V	Metastatic MM Unresectable SCC	Ipilimumab followed by Pembrolizumab	MM: Partial response SCC: Stability for 31 months and then progression A new onset eyebrow BCC surgically removed
Rubatto et al. 2021 [9]	XP	Locally advanced SCC, Localized SCCs and BCCs	Cemiplimab + Proton beam radiotherapy	SCC: partial response (C7)
Present Case	XP-V	Metastatic SCC	Pembrolizumab	SCC: partial response (C3)

AK: Actinic Keratosis; BCC: Basal Cell Carcinoma; C: number of cycle; ICI: Immune Checkpoint Inhibitor; M: Male; MM: Metastatic Melanoma; MT: Metastasis; NMSC: Non Melanoma Skin Cancer; SCC: Squamous Cell Carcinoma; XP: Xeroderma pigmentosum; XP-V: Xeroderma pigmentosum variant.

Acknowledgements

The authors thank the patient for granting permission to publish this information and Elisabeth Homassel for her technical assistance.

Disclosure statement

No potential conflict of interest was reported by the author(s).