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Familial pancreatic cancer increased risk for other malignancies in kindred

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October 14, 2014

Patients with familial pancreatic cancer were twice as likely to have a first-degree relative with an extra-pancreatic malignancy compared with patients with isolated cases of pancreatic cancer, according to study results.

Those with familial pancreatic cancer were more likely to have precursor lesions and were less likely to be smokers, results showed.

Andrew Biankin

Andrew Biankin, MBBS, PhD, of Wolfson Wohl Cancer Research Center at the University of Glasgow in Scotland, and colleagues sought to identify characteristics of familial pancreatic cancer — defined as cases of pancreatic cancer in which the patient had at least one other first-degree relative with the disease — that distinguished it from sporadic cases of pancreatic cancer.

The analysis included 766 patients with pancreatic ductal adenocarcinoma, 8.9% of whom (n=68) had familial pancreatic cancer.

Researchers determined median survival was comparable for patients with familial or sporadic pancreatic cancer regardless of whether they underwent resection (19.8 months vs. 17.4 months; P=.14) or did not undergo resection (7.2 months vs. 6.8 months; P=.61).

Mean age at diagnosis was similar between patients with familial or sporadic pancreatic cancer (65.8 years vs. 66 years; P=.89). However, the mean age of diagnosis was significantly younger in the next generation in the instance of parent-child familial pancreatic cancer (72.9 years vs. 60.6 years; P˂.0001).

A similar proportion of patients with familial or sporadic pancreatic cancer had a previously diagnosed malignancy (14.7% vs. 10.3%; P=.26).

Patients with familial pancreatic cancer were significantly more likely to have a first-degree relative with an extra-pancreatic malignancy (44.1% vs. 21.2%; P˂.0001).

First-degree relatives of patients with familial pancreatic cancer were significantly more likely to develop melanoma (8.8% vs. 0.6%; P˂.0001) or endometrial cancer (2.9% vs. 0.6%; P=.03) compared with first-degree relatives of patients with sporadic pancreatic cancer.

Researchers also noted patients with familial pancreatic cancer were more likely to have precursor lesions in their resected specimens (36.8% vs. 23.9%; P=.03) and were less likely to be active smokers at the time of diagnosis (8.8% vs. 28.2%; P=.0003) than patients with sporadic pancreatic cancer.

“These findings are important because they suggest that the genes we inherit from our parents likely play a significant role in our lifetime risk of developing pancreatic cancer,” Biankin said in a press release. “Secondly, they emphasize that when assessing someone’s individual risk of developing pancreatic cancer, it may be important to assess not just family history of pancreatic cancer but other malignancies, too. Finally, our data emphasize the importance of smoking abstinence.”

Disclosure: One researcher reports advisory board roles with and grants, honoraria and nonfinancial support from AstraZeneca, Novartis and Pfizer.

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PERSPECTIVE
Outcomes in pancreatic cancer have remained abysmal for decades. Epidemiology studies on familial disease are important because these patients are most likely to benefit from experimental screening and genetic studies. This field is underdeveloped, and limited to a handful of registries worldwide.
Humphris and colleagues provide welcome data on familial pancreatic cancer. They report clinical and pathological characteristics in 766 patients with pancreatic ductal adenocarcinoma (PDAC). Their cohort was accrued for genomic studies from 12 Australian hospitals, so the vast majority of patients had resected PDAC. Approximately 9% of patients were classified as having familial pancreatic cancer, meaning they had at least one first-degree relative with PDAC. The remainder were called “sporadic pancreatic cancer” (SPC). The major positive findings were: increased incidence of precursor lesions in resections from familial pancreatic cancer cases; increased extra-pancreatic cancers in familial pancreatic cancer families (particularly endometrial cancer and melanoma); and genetic anticipation among familial pancreatic cancer (ie, disease at younger ages in offspring). No significant differences were detected for age of onset or survival between familial pancreatic cancer and sporadic pancreatic cancer.
This study is descriptive in nature. Many statistical tests were performed, so the results should be interpreted cautiously. Nonetheless, the findings together support the notion of a distinct underlying genetic architecture for familial pancreatic cancer. Mutations in genes yet to be linked to PDAC cause the majority of inherited PDAC. The results of this study by Humphris and colleagues might guide researchers in the selection of patients for genomic studies, perhaps with an increased focus on families with an excess of other cancers besides PDAC and patients with precursor lesions.
Currently, we only have limited data that describe the contribution of the known genetic syndromes like BRCA1/2 and mismatch repair gene mutations to PDAC. Do relatives in this study with melanoma and endometrial cancer reflect familial atypical multiple mole melanoma syndrome and Lynch syndrome? With the decreased cost of next-generation sequencing, future studies should define how many patients with PDAC have known genetic syndromes and clarify the clinical implications. These studies will be important, because emerging data suggest that patients with genetic syndromes may have unique response to certain drug therapies.

Steven Gallinger, MD, MSc, FRCS, and Robert C. Grant, MD, MA
University of Toronto

Disclosure: Gallinger and Grant reports no relevant financial disclosures.