Fatigue, Weight Loss, and Abdominal Cramping in a 70-Year-Old Man

Tomislav Dragovich, MD, PhD; Shailja B. Amin, PA-C

Disclosures

December 19, 2014

Resectable disease accounts for less than 10% of pancreatic cancer cases (stage I-IIB). The tumor must be confined to the pancreas and peripancreatic nodes and not encase the celiac axis or superior mesenteric artery.[10] A Whipple procedure (pancreaticoduodenectomy) entails resection of the distal third of the stomach, gallbladder, cystic and common bile ducts, duodenum, and proximal jejunum. A modified Whipple procedure is a pylorus-preserving pancreaticoduodenectomy.[10]

Even after resection, the risk for local recurrence is more than 70%, which suggests a strong role for adjuvant therapy.[2] Resection is usually followed by adjuvant chemoradiation (with continuous 5-fluorouracil or capecitabine as a radiation sensitizer) and/or adjuvant gemcitabine-based chemotherapy for 4-6 months.[11]

Some cases are classified as borderline resectable, with focal tumor abutment of the visceral arteries or veins.[11] Although this is not a contraindication to resection, many pancreatic cancer centers advocate the use of neoadjuvant chemotherapy or chemoradiation therapy followed by resection.[12]

For true locally advanced unresectable disease, induction with infusional fluorouracil plus leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) or gemcitabine combination therapy is often followed by chemoradiation therapy.[11] Unfortunately, only a small fraction of patients (<10%) are downstaged and are able to undergo R0 or R1 resection.[13]

Around 50% of patients with newly diagnosed pancreatic cancer present with metastatic disease. In this setting, palliative chemotherapy is recommended.[2] First-line treatment options are influenced by the patient's performance status and age. Options include FOLFIRINOX, gemcitabine plus nab-paclitaxel, or gemcitabine monotherapy for elderly and frail patients.[13]

This case is of interest because of the patient's personal history of breast cancer, melanoma, and pancreatic cancer. Although the proportion of pancreatic cancers linked to these mutations is small, numerous studies have been aimed at finding optimized screening and treatments for this population.[14]

BRCA2 is a tumor suppressor gene involved in DNA repair. BRCA2 mutation predisposes individuals to breast cancer; the risk for male breast cancer is 5%-10%. A 3.5-fold, or 7%, risk of developing pancreatic cancer is also noted. BRCA2 is the most common known cause of familial pancreatic cancer, accounting for 17% of cases. A BRCA tumor suppressor gene is involved in DNA cross-linking damage; pancreatic cancer cell lines with BRCA mutations are sensitive to cross-linking agents, such as mitomycin C and cisplatin chemotherapy.[15]

Preclinical data also shows that targeting poly(ADP-ribose) polymerase may be effective against BRCA-mutated cells. In tumor cells, inhibition of PARP results in the development of DNA lesions that require intact BRCA for repair; thus, tumor cells that have defective BRCA lack the ability to repair DNA, rendering them more susceptible to cell death. Ongoing studies are combining PARP inhibitors with DNA-damaging chemotherapy for targeting tumors with BRCA mutations.[16]

PALB2 is a gene that encodes BRCA2-binding proteins and, therefore, has a molecular relationship with BRCA2. PALB2 mutations have been shown to be associated with an increased risk for familial pancreatic cancer and have a prevalence in 1%-2% of patients with familial breast cancer.[16]

A study of 94 patients with a personal history of BRCA1/2-negative breast cancer or a family history of pancreatic cancer found a prevalence of 2.1% for PALB2 mutation. Although further studies are needed to determine the clinical use of PALB2 mutations in patients diagnosed with pancreatic cancer, it may be useful for early screening in high-risk individuals.[16]

Another consideration is FAMMM, which is caused by a p16 tumor suppressor gene mutation. It is characterized by familial occurrence of malignant melanoma of the skin and pancreatic cancer. A retrospective study conducted from the Dutch FAMMM registry concluded that the estimated risk for pancreatic cancer in p16 gene mutations by age 75 years was 17%.[17] Although this syndrome is a consideration, a stronger family history of cancer is more common than is found in this case.

Currently, no screening tests are routinely recommended for average-risk individuals. Certain groups can benefit from screening to detect early pancreatic neoplasms, which include hereditary pancreatitis and inherited cancer susceptibility syndromes. Two precursor lesions to pancreatic cancer have been identified: intraductal papillary mucinous neoplasm and high-grade pancreatic intraepithelial neoplasia.

A prospective study from the American Cancer of the Pancreas Screening Consortium used CT, MRI, and EUS to screen 225 high-risk asymptomatic individuals; 92 (43%) were found to have a pancreatic mass or dilated pancreatic duct.[18] Of those, 82 were intraductal papillary mucinous neoplasms and three were pancreatic neuroendocrine tumors. Potential candidates for screening include patients with Peutz-Jeghers syndrome; those with hereditary pancreatitis; those who have three or more first-, second-, or third-degree relatives with pancreatic cancer; or known carriers of mutations associated with high risk for pancreatic cancer.[14]

In this case, although no strong family history is noted, the coincidence of breast and pancreatic cancer diagnosis warrants additional genetic risk evaluation and possibly further testing for BRCA2 and PALB2 germline mutations.

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