Objective

Immune therapy with the PD1 inhibitor pembrolizumab has been approved to treat unresectable/metastatic solid tumours exhibiting mismatch repair (MMR) deficiency. Lynch syndrome (LS), caused by autosomal dominant germline mutations of a MMR gene, predisposes to the development of MMR-deficient cancers. We report a case of MSH2-LS with an MMR-intact pancreatic ductal adenocarcinoma (PDAC) ineligible for treatment with pembrolizumab.

Design

Immunohistochemistry of MMR proteins was performed in each malignancy developed in a MSH2-LS patient to determine MMR status.

Results

The patient carried a pathogenic MSH2 germline mutation and had a history of LS-type cancers, including endometrial carcinoma, colorectal adenocarcinoma, urothelial carcinoma of the bladder and PDAC. Three malignancies (endometrial, colorectal, urothelial) lacked MSH2 and MSH6 expression, consistent with MSH2-associated tumorigenesis. However, MSH2 and MSH6 expression were intact in the PDAC, suggesting the sporadic occurrence of the pancreatic tumour unrelated to the germline MSH2 mutation. These inconsistent MMR statuses among the tumours rendered the patient ineligible for the immunotherapy pembrolizumab.

Conclusion

Testing for MMR protein expression is recommended for each tumour in patients with LS, especially pancreatic, as discordant results may have profound effects on treatment opportunities. To our knowledge, this is the first documented case of MMR-intact PDAC in a patient with MSH2-LS.

Background

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive cancers with poor survival. The dense desmoplastic stroma in PDAC contributes to treatment resistance. Among the components comprising the tumor stroma, hyaluronan (HA) has been demonstrated to play a critical role in tumor progression and survival. Previous preliminary studies have suggested differences in HA expression in primary and metastatic foci of PDAC. However, the effects of treatment and location of HA expression as a biomarker signature remain unknown; this study sought to compare HA expression in primary and metastatic sites of PDAC.

Methods

Tissue from primary and metastatic PDACs were obtained from Cedars-Sinai Medical Center along with associated clinical data. Tissue slides were stained for H&E, HA, and CD44. Associations between HA levels and the evaluated variables were examined including progression free survival and overall survival.

Results

HA score was significantly higher in primary PDACs compared to sites of metastases (p = 0.0148). Within the metastases, HA score was significantly higher in liver metastases compared to metastases at other sites (p = 0.0478). In the treatment-naive liver metastasis cohort, patients with HA high status had decreased progression free survival and overall survival compared to patients with HA low status (p = 0.0032 and p = 0.0478, respectively).

Conclusions

HA score is variable between primary PDAC, PDAC metastatic to the liver, and PDAC metastatic to other sites. Within liver metastases, patients with HA high status had decreased progression free survival and overall survival compared to patients with HA low status. HA levels can serve as a potential biomarker to guide pancreatic cancer treatments and trial design for agents targeting the stroma.

Introduction

Hyaluronan (HA) accumulation is associated with tumorigenesis and aggressive tumor behavior.

Aims

We investigated the biomarker potential of HA in non-small cell lung cancer (NSCLC).

Methods

HA levels were scored using affinity histochemistry in 137 NSCLC samples stratified by HA score ≤10, 11-20, 21-30, and >30 with HA-high defined as ≥25% expression in the extracellular matrix (ECM) of the tumor surface area. Overall survival (OS) and time to progression from initiation of taxane therapy (TTP) were compared using log-rank tests based on HA score.

Results

Of 122 patients with recurrent/metastatic NSCLC, 93 had mean HA scores that were not significantly different across clinicopathologic variables. Frequency of HA-high tumors did not differ by histology (34/68 adenocarcinomas vs. 12/25 squamous tumors, Fisher's p = 1.0000). Median OS for recurrent/metastatic adenocarcinoma was 35.5 months (95%, 23.6-50.3) vs. 17.9 months for squamous (95%, 12.7-37.0, log-rank test, p = 0.0165). OS was not significantly different by HA quartiles, high or low (<25) HA score and tumor histology, and HA biopsy site (all p > 0.05). Median TTP (n = 98) significantly differed by HA quartile (2.8 months for HA score ≤10; 5.0 months for 11-20; 7.9 months for 21-30; 3.9 months for >30, p = 0.0265). Improved TTP trended in HA-high over HA-low tumors (n = 98, p = 0.0911).

Conclusion

In this NSCLC cohort, tumor HA level represents a potential biomarker for TTP, which remains a cornerstone of NSCLC therapy. Further validation is warranted to identify the HA accumulation threshold associated with clinical benefit.