1. Recognize the risk factors for inherited predisposition to cancer and describe the major mutations causing breast, colon, and other cancers.

2. Choose the appropriate therapeutic strategy for patients with BRCA mutations, Cowden disease, Li-Fraumeni syndrome, and familial adenomatous polyposis (FAP).

3. Describe the role and benefits of genetic counseling in the management of patients with suspected inherited predisposition to cancer.

4. Summarize the contributions of recent advances in molecular genetics, diagnosis and staging, surgical procedures, and adjuvant therapies in improving mortality of patients with pancreatic cancer.

5. Employ surgical modifications that reduce blood loss and improve operative mortality during resection of pancreatic cancers.

Evaluation of Patients for Familial Cancer Risk
Lori L. Ballinger , MS, Senior Genetic Counselor, University of New Mexico Cancer Research and Treatment Center, Albuquerque

Cancers with inherited components: include breast, breast/ovarian, colon, renal, melanoma, thyroid, and gastric cancers; genetic component found in 5% to 10% of all malignancies, including leukemias; individuals with predisposition to inherited cancers have higher lifetime risk of developing cancer at earlier age; highly penetrant mutations cause large burden in afflicted families; many genes increase risk for multiple types of cancer; surveillance for cancer in high-risk families different from that in general population; surgical interventions efficacious in reducing risk for inherited cancer

Patients at risk: individuals who have 2 relatives on same side of family with cancer; inherited predisposition suggested by early onset, presence of multiple types of cancer (eg, colon and endometrial cancers), and bilateral cancers (except ovarian)

Genetics: most syndromes inherited as autosomal dominant mutations with reduced penetrance (ie, percentage of patients with mutation who develop disease); phenotype may appear to skip generations

Breast cancer: multiple syndromes; BRCA—carriers have 50% to 85% risk for breast cancer; greatly increases risk for ovarian, prostate, and pancreatic cancers; men who carry mutation have 100-fold higher risk for breast cancer than general population and are at increased risk for early-onset prostate cancer and pancreatic cancer; Cowden disease (PTEN mutation)—35% rate of breast cancer, with increased risk for endometrial and thyroid cancers and renal malformation; no increase in rate of ovarian cancer; hereditary diffuse gastric cancer (CDH1 mutation)—40% risk for lobular cancer, signet-ring cell carcinoma of colon, and diffuse gastric cancers; Li- Fraumeni syndrome (p53 or TP53 mutations)—25% to 30% lifetime risk for breast cancer and increased risk for hematologic cancers, sarcomas, soft tissue sarcomas, and bone, brain, and adrenocortical cancers; rate for second primary breast cancer, 40% to 60% per year (compared to 1%-20% in general population)

BRCA mutations: prophylactic mastectomy in unaffected carriers reduces risk for breast cancer by 90%; in women with breast cancer, bilateral mastectomy reduces risk for second primary breast cancer; removal of ovaries by 40 yr of age reduces risk for breast cancer by 50% (short-term hormone replacement therapy [HRT] beneficial for such patients); prophylactic bilateral salpingo-oophorectomy reduces risk for ovarian cancer by >95% when guidelines of Society of Gynecological Oncologists followed (include removal of ovaries, remnants and ovarian ligament, plus or minus peritoneal washings, and examination of abdominal cavity for occult ovarian cancers, which occur at rate of 3%-11% in women ≈40 yr of age)

Cowden disease: multiple cutaneous and mucosal hamartomas (disorganized but not dysplastic tissues) in colon, mouth, nose, face, and tongue; increased risk for other cancers and for benign glial mass of cerebellum (Lhermitte-Duclos disease)

Li-Fraumeni syndrome: patients with TP53 mutations have highest risk for breast followed by bone and brain cancers; suggested by presence of soft tissue sarcoma in family history; patients have 85% to 93% lifetime risk of developing cancer and higher risk for second primary cancers resulting from radiation or chemotherapy

Colon cancer: associated with many syndromes; 6% prevalence of colon cancer in general population

Familial adenomatous polyposis (FAP): polyps may develop in individuals as young as 10 yr of age; also associated with higher risk for extracolonic tumors, eg, upper gastrointestinal (GI) tumors, desmoids, osteomas (Gardner’s variant); identical to Gardner’s syndrome; adenomatous polyposis coli (APC) mutations also associated with brain tumors (Turcot variant), eg, glioblastoma; mutations in Turcot variant of Lynch syndrome associated with medulloblastomas

Surgical management: National Comprehensive Cancer Network (NCCN) guidelines recommend considering colectomy if polyp burden >20, some polyps >1 cm in size, or advanced histology found in any polyp; untreated polyposis carries 100% risk for cancer; some patients with many polyps (but not frank polyposis) may have mutations in same gene as FAP; mutations near 3’- or 5’-end of gene may cause attenuated form of FAP with fewer colonic adenomas; important to count polyps, due to high degree of variability within families; upper GI lesions—in fundic gland, polyps and duodenal adenomas common; testing recommended if >20 cumulative adenomas; polyp burden determines need for colectomy; attenuated phenotype can result from mutations in APC gene or in autosomal recessive inherited cancer syndromes, eg, MutYH (MYH)-associated polyposis (MAP)

Hereditary nonpolyposis colon cancer (HNPCC): syndrome involves multiple cancers; synonymous with Lynch syndrome; confers highest risk for colorectal cancer, followed by endometrial cancer (often sentinel cancer in women, with age at onset several years earlier than that of colon cancer); occurs predominantly on right side; 20% risk for stomach cancer; pancreatic and other biliary tree cancers seen; also transitional cell, uroepithelial, and ovarian cancers occur at rate of 10%; histopathologic examination important for diagnosis because not all patients present with usual criteria (eg, presence of colon cancer at <50 yr of age, or 3 affected family members); suggested by mucinous, signet-ring type of histopathology, Crohn’s-like inflammation, and tumor-infiltrating lymphocytes

Management of Lynch syndrome: perform colonoscopy every 1 to 2 yr because Lynch syndrome involves defect in DNA mismatch repair, and cancer-causing mutations accumulate rapidly; perform upper endoscopy every 2 yr, beginning at 30 yr of age; perform endometrial ultrasonography and biopsy every year, beginning at 25 yr of age; remove reproductive organs from women after childbearing completed (patients may have HRT until 45-50 yr of age); perform urine cytology annually to detect transitional cell carcinomas of uroepithelial tissues; colectomy is option in patients with cancer phobia, those who do not comply with screening, and those who have existing colon cancer (18% of patients with Lynch syndrome have synchronous and 30%-45% have metachronous colon cancer)

Juvenile polyposis: children have associated dysmorphology and abnormalities of heart or malrotation of gut; appearance of juvenile polyps different from that of adenomatous polyps; can occur in adults; often mistaken for hyperplastic polyps on pathologic examination

Other inherited syndromes increasing risk for colon cancer: hereditary diffuse gastric cancer—increases risk for signet-ring cell carcinoma of colon as well as breast cancer; hyperplastic polyposis syndrome; familial colon cancer syndrome X—criteria include 3 family members with colon cancer (one first-degree relative of other 2), 2 generations affected, 1 cancer diagnosed before 50 yr of age; patients do not have mutations in genes associated with Lynch syndrome; hereditary mixed polyposis syndromes—patients have hyperplastic polyps, juvenile polyps, and adenomas, alone or in combination

Genetic risk assessment (counseling): pretest and posttest counseling standard of care for any family undergoing genetic testing; American College of Obstetricians and Gynecologists (ACOG), American Society of Clinical Oncologists, and Society of Gynecological Oncologists recommend counseling to obtain 3-generational pedigree to assess risk, educate patients about genetics and individual risk, choose appropriate test(s), explain test procedure, risks, benefits and limitations, and discuss alternatives to testing and management options

Genetic counselors: trained in medical genetics, counseling, conveying complex information to patients, and assessing family history; familiar with available tests; interpret test results; formulate follow-up plans with patients and other at-risk family members

Questions and answers: legislation to prevent genetic discrimination—New Mexico has legislation prohibiting use of genetic information to exclude applicant from health insurance; prohibits demand for genetic information by employers and performance of genetic testing without employee’s knowledge; similar to Genetic Information Nondiscrimination Act (GINA); genetic discrimination defined as discrimination against individuals without disease who have genetic predisposition

Pancreatic Cancer: No Room for Nihilism
Howard A. Reber, MD, Professor of Surgery, and Chief of Gastrointestinal Surgery, David Geffen School of Medicine at the University of California, Los Angeles

Background: 38,000 new cases of pancreatic cancer expected in the United States this year; death rate from pancreatic cancer fourth highest among cancers and second highest among GI cancers (after colorectal cancer); >37,000 cases reported in United States in 2007

Molecular genetic advances: patients who show progression from normal cuboidal to columnar epithelium in pancreatic duct, with continued loss of architecture, develop pancreatic intraepithelial neoplasia (PanIN1 or PanIN2); PanIN3 formerly called carcinoma in situ; next stage involves invasive pancreatic cancer; morphologic changes accompanied by changes at molecular level; information about genesis and evolution of disease may enable earlier detection and more effective treatment with pharmaceuticals targeted to genes or their products

Advances in diagnosis and staging: helical computed tomography (CT)—can determine resectability of pancreatic neoplasm, revealing presence or absence of liver metastasis and assessing extent of vascular invasion; resection possible in >90% of patients with grade 1 and 50% with grade 2 levels of vascular involvement; almost no tumors in patients with grades 3 or 4 disease resectable

Improvements in surgery

Operative mortality: most patients receive either standard or pylorus-preserving Whipple operations; previously, rate of operative mortality for standard Whipple operation approached 20% to 25%, with even lower rates of success; currently, operative mortality <5%; lowest mortality associated with most experienced surgeons and centers

Surgical outcomes: 50% of patients who survive 5 yr after surgery will eventually die from disease; 5-yr rates of survival range from 7% to 20%

Reduction of operative blood loss: high level of blood loss during cancer surgery may negatively affect prognosis after resection of many cancers; may result from immunosuppressive effects of blood loss and transfusion; studies report efforts to limit blood loss resulted in decrease from mean of 700 mL to 400 mL per Whipple operation; among 200 patients observed, average overall 5-yr rate of survival 27%; those who received surgery before efforts to reduce blood loss had 16% rate of survival; those with lower loss of blood during surgery had 35% survival

Adjuvant therapies: most patients with pancreatic cancer recommended to receive postsurgical chemotherapy; role of radiation therapy remains controversial

Gemcitabine: standard chemotherapeutic agent; study showed statistically significant (but very small) difference between survival in patients receiving gemcitabine (5.6 mo) vs. 5-fluorouracil (5FU; 4.4 mo); erlotinib (Tarceva)— acts as HER1/EGF receptor antagonist; only agent shown to improve survival when combined with gemcitabine (from 17% 1-yr survival rate in patients receiving gemcitabine plus placebo to 24% in patients receiving gemcitabine plus erlotinib); gemcitabine plus erlotinib currently recommended as first-line therapy

Chemoradiation: study—patients with resected pancreatic cancer randomized to groups undergoing observation (no adjuvant therapy), chemoradiation therapy, chemotherapy, or chemoradiation plus chemotherapy; found no statistically significant difference in 5-yr survival among those who had no adjuvant therapy and those who had chemoradiation, with or without chemotherapy; higher rate of survival (29%) seen among patients receiving chemotherapy alone

Down-staging chemotherapy; study—selected group of 25 patients with unresectable tumors underwent chemotherapy with regimen of 5FU, leucovorin, mitomycin-C, and dipyridamole; 3 patients survived long-term

Questions and answers: correlation of transfusion and blood loss with survival—transfusion also correlates with survival (although significance not as high as with blood loss) for unknown reasons; cancers of body and tail of pancreas—rates of survival among patients with cancers of body and tail of pancreas lower because disease presents later, tumors usually unresectable, and they usually recur; speaker has seen few patients survive 5 yr; data suggest these tumors similar to those in head of gland at same stage; explanation for higher survival rates after surgery at speaker’s institution—higher survival rates best explained by effects of lower blood loss during surgery