Discussion:
This case report describes a patient in whom multiple metastases of SCC
emerged against a background of XP that was confirmed by a DNA repair
test. Nivolumab achieved dramatic tumor shrinkage in this patient,
despite the fact that his TMB, MSI, and CPS were not high.
Table 1 summarizes the reports in the literature on patients treated
with ICI for malignant lesions arising against a background of XP
[12-19]. The first report was published by Hauschild et al., who
described the clinical outcome in a patient with XP treated with
pembrolizumab, another type of anti-PD-1 monoclonal antibody [12].
Eleven cases (including our present case) with variable histology,
including SCC, basal cell carcinoma, and angiosarcoma, have been
described. Six of the previous cases with XP-C, two with XP-E, and one
with XP-V; the subtype was not mentioned in one case. Three patients (3,
10, and 11) were treated with nivolumab, seven (1, 2, and 4–8) with
pembrolizumab, and one (patient 9) with ipilimumab (the CTLA-4
monoclonal antibody) followed by pembrolizumab. The overall response
rate was 100%, and 9 of the 11 patients (82%) achieved durable
responses during the observation period. None of the patients
experienced serious adverse events. Concomitant skin lesions decreased
in size after introduction of ICI in five patients (1, 7-9, and 11).
Therefore, all metastatic lesions or concomitant skin lesions were
successfully treated with ICI in these cases.
It is thought that the high mutational burden in XP-associated SCC
accumulated by years of sun exposure might respond well to ICI therapy
[18]. The KEYNOTE-158 study in 2020 found that patients with a high
TMB had a good response to pembrolizumab [20]. Therefore, TMB could
be a useful predictor of the response to pembrolizumab in patients with
previously treated recurrent or metastatic advanced solid tumors given
that the indications for pembrolizumab have been expanded to include
patients with high TMB. Not all of the 11 patients in this report
underwent next-generation sequencing, but at least four patients (1, 5,
6, and 10) were reported to have a high TMB. Our case (patient 11) was
the only one with a low TMB. However, it is not clear how accurately the
submitted samples reflected the status of relapsed tumors. This is one
of the limitations of our report.
Solid MSI-H tumors are also an indication for pembrolizumab. However,
although most MSI-H tumors have a high TMB, not all tumors with a high
TMB are MSH-H [21,22]. The coexistence of MSI-H and high TMB is
often observed in gastrointestinal cancer; however, in malignant
melanoma, SCC, and lung cancer, high TMB is relatively common, whereas
MSI-H is not [23]. Indeed, MSI-H was not found in any of the 11
patients in the present report. Therefore, the relationship between
MSI-H and the therapeutic effect of ICI in patients with XP is not
clear.
CPS is an index of PD-L1 expression and, like TMB and MSI-H, is used to
predict the therapeutic effect of pembrolizumab. Several virus-related
cancers, including nasopharyngeal carcinoma (caused by Epstein-Barr
virus), oropharyngeal carcinoma (caused by human papillomavirus), and
Merkel cell carcinoma (caused by Merkel cell polyomavirus) are
considered to arise as a result of PD-L1 expression against a background
of chronic inflammation [24-26]. Chronic inflammation in response to
UV exposure may also increase the CPS in patients with XP. PD-L1
expression was detected in three patients (2, 6, 11) in our series;
however, case 11 (our patient) had a low CPS. As mentioned earlier in
relation to the TMB in our patient, the samples submitted for analysis
may not have been fully representative in cases with tumor recurrence.
When our patient developed multiple distant metastases, nivolumab was
the only ICI covered by the Japanese health insurance system for
platinum-refractory RM-HNSCC. Pembrolizumab was not approved for
platinum-sensitive RM-HNSCC at that time. Therefore, platinum-based
chemotherapy was administered before nivolumab. However, the dose of
carboplatin was reduced considerably for the following reasons. An in
vitro study suggested that cisplatin may have enhanced cytotoxic effects
on normal cells in XP, reflecting the deficiency of DNA repair systems
[27-29]. Sumiyoshi et al. also reported that two patients with XP
died from severe adverse events attributed to cisplatin [10]. One of
these patients with XP-V and developed severe hearing impairment, renal
dysfunction, and febrile neutropenia after treatment with cisplatin and
vinorelbine for stage IIIA non-small cell lung cancer. The other
patient, a family member of the first case, was treated with cisplatin
and 5-fluorouracil for stage IIB esophageal basaloid SCC and developed
severe hearing impairment, renal/hepatic dysfunction, and
myelosuppression. Both patients died as a result of multiple organ
failure, one at 59 days and the other at 21 days after initiating
platinum-based chemotherapy. Therefore, extreme care should be taken
when using a platinum agent in a patient with XP. Fortunately, the
indications for pembrolizumab have now been expanded to allow patients
with head and neck cancer as well as those with TMB-H to be treated with
this agent without the need for treatment with platinum in Japan.
In this report, we described a patient with XP who was successfully
treated with nivolumab and showed a marked and durable response. Apart
from factors such as MSI, TMB, and CPS, a decrease in UDS may also be a
predictor of ICI response. Although the limitation of this report is
that it is a single case report, it is a valuable report because of the
rarity of this disease. If available, an anti-PD1 antibody should be
used first for unresectable carcinoma caused by XP. To our knowledge,
this is the first report of successful use of ICI to treat XP in Japan.