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Page 18 of 26 Skorupan et al. J Cancer Metastasis Treat 2023;9:5 https://dx.doi.org/10.20517/2394-4722.2022.106

SUMMARY AND CONCLUSIONS
Consensus guidelines for rare exocrine pancreatic tumors like ASCP and PACC have not been published.
Consequently, these tumors are most frequently treated using standards of care established for PDAC.
While ASCP may represent an extreme variant of the basal transcriptomic subtype of PDAC, PACC shares
few morphologic, histologic or molecular characteristics with PDAC and application of PDAC treatment
paradigms to PACC is inappropriate.

Based on our review of the existing literature, it is clear that ASCP is a more aggressive tumor than PDAC
and responses to current PDAC treatments are inadequate. Solving the puzzle of how best to control ASCP
is likely to benefit the larger PDAC population, given the overlap of ASCP and the most aggressive subtypes
of PDAC that harbor SF or SD. Research into treatment paradigms for basal-type PDAC, which is largely
synonymous with PDAC with SF/SD, has expanded significantly over the last several years, but has resulted
in limited clinical advances thus far. Recent studies have suggested that basal-type PDAC is less sensitive to
platinum chemotherapy than classical-type [189,190] . Intriguingly, the available ASCP data hint at platinum
chemotherapy providing benefits to this patient population. It is worth considering whether the more
extensive squamous differentiated component of ASCP may have sensitivities to unique chemotherapy
regimens that are less effective in pure adenocarcinoma. Perhaps more importantly for this population, new
drugs targeting activated KRAS appear to be imminent and could turn the tide in this KRAS-driven disease.

PACC is a tumor that shares few characteristics with PDAC other than arising in the pancreas and
preferentially metastasizing to the liver. It is clear that surgical resection of this less aggressive tumor
provides significant benefit to early-stage patients, and investigation into the role of metastasectomy in
treating PACC is also warranted. A benefit of adjuvant chemotherapy to cure early-stage patients is likely to
present for PACC patients with lymph node involvement, but unclear in patients with more limited disease.
Systemic therapy with platinum agents produces the best outcomes in PACC patients. Regimens with a
fluoropyrimidine backbone are preferred in treating PACC, as the use of gemcitabine in this disease has
resulted in inferior outcomes. All patients with PACC should undergo molecular testing for somatic
mutations as these occur at high incidence and are frequently actionable, and treatment with matched
therapy has been highly beneficial in case reports. In addition, the high rate of MSI-H/dMMR occurrence in
PACC should prompt universal evaluation of these markers which could demonstrate sensitivity to
immunotherapy. Given the extreme rarity of this disease, a coordinated research effort across many
institutions will likely be required to generate sufficient cases to inform evidence-based clinical care for
PACC.

Dedicated clinical trials for ASCP and PACC are uncommon. These studies are difficult to accrue given the
rarity of the diseases. It is also unclear how many ASCP and PACC patients understand that their pancreatic
cancer is different from “standard” pancreatic cancer and would be interested in seeking more tailored
treatment. We have found that at least one-third of pancreas cancer trials testing medical interventions
permit the accrual of patients with any exocrine pancreatic tumor rather than limiting eligibility to PDAC
[Figure 4]. While this offers benefits to patients by providing additional treatment options, these treatments
may not be well justified in ASCP or PACC and are unlikely to advance our understanding of these rare
diseases when it is likely that, at most, a single rare tumor patient will be enrolled, and their availability
could further reduce the patient pool willing to seek out ASCP- or PACC-specific studies.

In summary, rare exocrine tumors of the pancreas present a clinical challenge since treatment guidelines are
lacking. However, existing data, as described above, could form the nucleus of what constitutes best practice
for these diseases.