Oncology Update. Franklin Chen, MD. Novant Health Oncology Specialists. Making healthcare remarkable

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1 Oncology Update Franklin Chen, MD Novant Health Oncology Specialists Making healthcare remarkable

2 Disclosures Speakers Bureau Onyx Principal Investigator BMS, Genetech, EMD Serono, Incyte

3 Objectives Lung cancer screening Breast cancer prevention BRCA 1 and 2 Lynch Syndrome 3 Novant Health: Enter Presentation Title in Footer Menu 5/22/2013

4 Lung Cancer Screening Even though it is the 3 rd leading cause of cancer in the US, it is the leading causing of cancer related death 228,190 cases, 159,480 deaths in US Amongst women, leading cause of cancer related death 5 year survival for all patients is approx 16% Prevention needs to be a key strategy at reducing total number of cases

5 Lung Cancer Screening Many characteristics of lung cancer suggest that screening could be effective: high morbidity and mortality, have a high prevalence in a certain population, clinical outcome dependent on stage at diagnosis Potential harms of screening: false positives leading to unnecessary surgery, radiation from serial imaging, follow up of lung nodules over period of years can cause anxiety No randomized study has shown mortality benefit for screening with CXR

6 Lung Cancer Screening National Lung Screening Trial (NLST) compared annual screening by low dose chest CT with CXR annually for three years in 53,454 high risk patients Men and women 55 to 74 with history at least 30 pack years of smoking Median follow up 6.5 years, 645 cases of lung cancer per 100,000 person years in CT group and 572 cases in CXR group Per 100,000 person years, 247 lung cancer deaths vs 309 in CXR For the typical NLST participant, screening would prevent 3.9 deathsover 6 years per 1000 persons, equal to screening 256 persons annually for three years to prevent one cancer related death over six years

7 Lung Cancer Screening LDCT is more effective than CXR at finding asymptomatic lung cancers Both CXR and LDCT have high rates of false positives leading to additional testing and procedures NLST demonstrated a lung cancer mortality benefit of 20 percent Cost effectiveness is an issue. Not only cost of screening test but also price of false positives

8 Lung Cancer Screening New findings prompt Category 1 recommendation for Smokers. In late 2011, the National Comprehensive Cancer Network published new guidelines that strongly recommend the use of LDCT as and effective screening tool for early detection of cancer among high risk cigarette smokers. High risk defined as adults with 30 pack year Recommendation prompted by study showing 20% fewer cancer related deaths among those screened by CT vs CXR Disease is often found too late for effective treatment $299 fee not covered by insurance More info (336) 794 XRAY

9 Breast Cancer prevention Most common non skin cancer in women 232,340 new cases 39,620 women will die Screening will detect but not prevent Both tamoxifen and raloxifene have been approved by FDA for prevention

10 Breast Cancer Prevention (Patient Selection) Age over 60 years Age over 35 years with a history of lobular carcinoma in situ (LCIS), ductal carcinoma in situ (DCIS), or atypical proliferative lesion of the breast (atypical ductal or lobular hyperplasia) (See "Atypia and lobular carcinoma in situ: High risk lesions of the breast".) Women between 35 and 59 years with a Gail model risk of breast cancer 1.66 percent over five years Women with known BRCA1 or BRCA2 mutations who do not undergo prophylactic mastectomy

11 Breast Cancer Prevention (Patient Selection) Google Gail Model NCI site, Breast Cancer Risk Assessment Tool (calculator) Takes into account 7 risk factors (Age, Age at first period, Age at the time of the birth of first child, family history, number of past breast biopsies, number of breast biopsies showing ADH, race/ethnicity) Calculates a five year and lifetime risk of developing breast cancer compared to an average woman Women with a five year risk of 1.67 percent or higher are classified as "high risk". This score (a five year risk of 1.67 percent or higher) is the cut off for the FDA guidelines on tamoxifen and raloxifene use for breast cancer risk reduction.

12 Breast Cancer Prevention (Possible Benefit) In the Breast Cancer Prevention Trial of 13,388 healthy women, those assigned to take tamoxifen developed 85 cases of invasive breast cancer compared to 154 cases in the individuals assigned to the placebo. Meta analysis by the US Preventive Services Task Force showed that administration of tamoxifen or raloxifene for five years is effective in reducing the incidence of breast cancer by 7 9 cases per 1000 women. Benefit is greatest in women with a Gail model risk score of >5

13 Breast Cancer Prevention (Possible Risk) An increased in invasive endometrial cancer compared to placebo (2.24 versus 0.68 cases per 1000 women). The risk of endometrial cancer was significantly increased only in women aged 50 years or older. A trend towards higher stroke rates (1.75 versus 1.23 cases per 1000 women, RR 1.42), which did not reach statistical significance. An increased risk of pulmonary embolism (0.69 versus 0.32 cases per 1000 women).

14 Breast Cancer Prevention (Summary) Among women at high risk for breast cancer, endocrine therapy can reduce the risk of both invasive and in situ cancer An individual s risk can be assessed with online calculators including the NCI site, Breast Cancer Risk Assessment Tool Both raloxifene and tamoxifen are options for postmenopausal women and tamoxifen is an option for premenopausal women There are newer hormonal therapies, the aromatase inhibitors which may become an option for prevention as well.

15 Hereditary Breast and Ovarian Cancer Although a family h/o breast or ovarian cancer is common, less than 10 percent of all breast cancers and 15 percent of all ovarian cancers are associated with an inherited genetic mutation Majority of hereditary breast and ovarian cancer cases are associated with mutation in the breast cancer type 1 or type 2 susceptibility genes (BRCA1 or BRCA 2) Account for approx 5% breast cancer cases in US BRCA 1 and 2 are tumor suppressor genes that are involved in repair of DNA breaks, control of cell cycle checkpoint, and chromosomal segregation

16 Hereditary Breast and Ovarian Cancer Mutations in BRCA1 and 2 are inherited in autosomal dominant fashion and are highly penetrant Lifetime risk of breast cancer estimated 50 85% Lifetime risk of ovarian cancer 15 40% Male carriers increased risk of both breast (still under 10%) and prostate cancer (five to seven fold) Increased risk of pancreatic cancer as well

17 Hereditary Breast and Ovarian Cancer Individual from a family with a known BRCA 1 or 2 Personal h/o ovarian cancer Personal h/o male breast cancer Personal h/o breast cancer (plus another high risk factor, for example, age <45, age <60 with triple negative, any age with >1 blood relative with breast or ovarian at any age, two breast primaries with first one <50, etc) Personal h/o breast or ovarian at any age and more than 1 close relative with pancreatic cancer Personal h/o pancreatic cancer with more than 1 close relative with breast or ovarian or pancreatic cancer Family history only but 1 st or 2 nd degree relative meeting above criteria

18 Hereditary Breast and Ovarian Cancer Clinical exam every 6 12 mos, annual mammograms, age 25 Discuss option risk reducing mastectomies Recommend salpingo oophorectomy, age (family hx) Consider chemoprevention options Advise of risk to family members, recommend genetic counseling for at risk family members

19 Lynch Syndrome Also called hereditary nonpolyposis colorectal cancer (HNPCC) Most common of the inherited colon cancer susceptibility syndromes Autosomal dominant caused by a germline mutation of several mismatch repair genes Accounts for 2 3 % colon cancer and 2% endometrial cancers Early age of diagnosis and multiple cancers Lifetime risk of colon cancer is 70% Others include ovary, stomach, small bowel, pancreas, hepatobiliary, renal pelvis, ureter

20 Lynch Syndrome Mismatch repair genes include MSH2 (39%), MLH1 (32%), PMS 1 and 2, MSH 6, and MLH3 which correct mismatch DNA base substitutions Mutations in these genes cause defective mismatch repair which cause genomic instability in regions of repetitive nucleotide sequences called microsatellites resulting in microsatellite instability Microsatellite instability is the molecular signature of Lynch Syndrome and can be tested in tumors (PCR) Immunohistochemistry can identify loss of MMR protein in tumors

21 Lynch Syndrome Bethesda Criteria Tumor testing in: CRC diagnosed in a patient < 50 years of age Presence of synchronous, metachronous CRC or LS related tumor regardless of age CRC with MSI H histology in patients <60 years of age CRC diagnosed in 1 or more 1 st degree relative with LS related cancer < 50 years of age CRC diagnosed in a patient with 2 or more 1 st or 2 nd degree relatives with LS related cancers

22 Lynch Syndrome Revised Amsterdam Criteria II At least 3 relatives with LS associated cancer One must be a first degree relative of the other two At least 2 successive generations must be affected At least 1 relative with cancer associated with LS should be diagnosed before age 50 years FAP should be excluded Tumors should be verified

23 Lynch Syndrome Surveillance for Mutation Carriers Colonoscopy at age 20 25y or 2 5 years prior to the earlier colon cancer if it is diagnosed before age 25 and repeat every 1 2 years Extracolonic: TAH BSO to be considered for woman finished with childbearing Yearly endometrial sampling

24 Genetic Cancer Syndromes Contact Information: Kate Hughes, MS, CGC Derrick L. Davis Cancer Center High Risk Clinic Phone:

25 Thank You 25 Novant Health: Enter Presentation Title in Footer Menu 5/22/2013