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Home , BRCA mutation, Breast cancer

Understanding And Ovarian Risk

Susan Domchek, MD Basser Professor in Executive Director, Basser Center for BRCA Director, MacDonald Cancer Risk Evaluation Center University of Pennsylvania www.basser.org Risk has many components

• Age

• Family history is important – Identifiable genetic risk is only one component

• Reproductive factors – Early protective for both breast and – Breast feeding protective – protective for ovarian cancer

• Environmental exposures – Alcohol for – “Talc” for ovarian cancer – Decreased risk of ovarian cancer with oral contraceptive pills

•

• Unknown factors How much ovarian cancer is “genetic”

BRCA1/2 "Other" SNP None known How much breast cancer is “genetic”

BRCA 1/2 "Other" genes Known SNP Predicted SNP None known Features of Hereditary Cancer • Cancer in multiple generations • Cancer at younger ages (< 50 years) • Individuals with multiple cancers • Clustering of rare • Cancer in the less usually affected gender • More common in certain ethnic groups

Collect your family history of cancer before discussing ! Not All BRCA Families are so Obvious • The risk is never 100% to develop cancer • Families with few women • The family is small • The family history is unknown or uncertain • Individuals died young of other causes • Women had removed for other reasons, which reduces both breast and ovarian cancer risk BRCA1 and BRCA2 Basics

• Everyone has BRCA1 and BRCA2 genes • BRCA genes repair damage to DNA within the cell and help to prevent us from getting cancer • When there is a in BRCA1 or BRCA2, an individual has increased cancer risks in adulthood • Both men and women can have BRCA • BRCA mutations can be passed on to children

BRCA1 BRCA2 BRCA Mutations in the Population • In the general population, 1 in 500 people will carry a BRCA mutation – 5-10% of breast cancers – 10-15% of ovarian cancers • Ashkenazi Jewish ancestry: 1 in 40 people will carry a BRCA mutation. This at least a 10x greater chance than the general population – 3 mutations account for ~90% – These are called “founder mutations” – 10% of breast cancers in individuals of Ashkenazi Jewish descent – 30-40% of ovarian cancers in individuals of Ashkenazi Jewish descent

Lifetime BRCA Risks for Women

Women Women Average with BRCA1 with BRCA2 in US mutation mutation without mutation Type of Breast 60-80% 50-70% 13% Cancer Ovarian 30-45% 10-20% 1-2% Pancreatic 2-3% 3-5% 1% - 3-5% 1-2%

www.basser.org Lifetime BRCA Risks for Men

Men Men Average man in with BRCA1 with BRCA2 US without mutation mutation mutation

Type of Breast 1-5% 5-10% 0.1% Cancer Prostate * 15-25%* 16%

Pancreatic 2-3% 3-5% 1%

Melanoma - 3-5% 1-2%

* Men with BRCA1 mutations may develop at a younger age than the general population. BRCA2 mutations are associated with an increased risk of prostate cancer, which also can be of earlier onset.

www.basser.org BRCA Management: Women • Breast Cancer Risk Management and Reduction – Breast cancer begins at 25 o Annual MRI o Annual mammogram starting at age 30 o Clinical breast exam every 6 months – Surgical option o Prophylactic double o 90% risk reduction o Personal decision – Prevention (hormonal intervention to reduce breast cancer risk) o Medications (such as ) o Removal of the ovaries

How Risk Changes Over Time: Breast Cancer

Blue bar indicates average risk (percent chance) that a woman with a BRCA1 mutation will develop breast cancer by each age noted across the bottom. The vertical line on each bar indicates a portion of the range of risks seen in different studies and is called the 95% confidence interval (Chen & Parmigiani 2007). How Risk Changes Over Time: Breast Cancer

Blue bar indicates average risk (percent chance) that a woman with a BRCA2 mutation will develop breast cancer by each age noted across the bottom. The vertical line on each bar indicates a portion of the range of risks seen in different studies and is called the 95% confidence interval (Chen & Parmigiani 2007). BRCA Management: Women • Ovarian Cancer Risk Management and Reduction – Ovarian begins age ~30-35 o Blood test (CA-125) every 6-12 months o Ovarian ultrasound every 6-12 months o These methods have not been proven effective – Prevention o Use of oral contraceptive pills – Surgical removal of the ovaries & fallopian tubes o Recommended between 35 and 40 o After childbearing is complete o Double risk reduction How Risk Changes Over Time: Ovarian Cancer

Blue bar indicates average risk (percent chance) that a woman with a BRCA1 mutation will develop ovarian cancer by each age noted across the bottom. The vertical line on each bar indicates a portion of the range of risks seen in different studies and is called the 95% confidence interval (Chen & Parmigiani 2007). How Risk Changes Over Time: Ovarian Cancer

Blue bar indicates average risk (percent chance) that a woman with a BRCA2 mutation will develop ovarian cancer by each age noted across the bottom. The vertical line on each bar indicates a portion of the range of risks seen in different studies and is called the 95% confidence interval (Chen & Parmigiani 2007). Timing of • We do not have a consistently effective way to screen for ovarian cancer. Transvaginal ultrasound and CA125 measurements are not sensitive and specific enough.

• Ovarian cancer risks vary by mutation and by age – BRCA1 mutations are associated with a higher risk of ovarian cancer (20-45%) and at somewhat earlier ages – BRCA2 mutations are associated with lower risks of ovarian cancer compared to BRCA1 (10-20%) and at more “typical” ages

• Can I just take out my fallopian tubes? – Active research question – We do not have a good level of evidence – Devil is in the details BRCA Management: Men • Breast screening begins at 35 o Self breast exams every 6-12 months o Clinical breast exams every 6-12 months o Consider mammograms at 40 (if enough breast tissue) • Prostate screening begins at 40 o Blood test (PSA) o Prostate exam BRCA Management: Men & Women

• Individuals with a family history of melanoma and/or should speak to their health care provider about a screening plan • Trials ongoing regarding pancreatic cancer screening particularly in families with pancreatic cancer • Healthy lifestyle choices appear to a role in cancer risk reduction and have proven effective at preventing other conditions, such as heart disease

Other Genes • While BRCA1/2 are well understood, other genes are associated with cancer risk – Such as PALB2, CHEK2, ATM for breast cancer – Rad51C/D and BRIP for ovarian cancer • In some instances, testing a person for multiple types of mutations may be warranted – Panel testing • Some of these genes are still not well understood and pose challenges for determining how care should be altered in mutation carriers – A genetics professional can help to determine the best approach to testing • If you are already a BRCA1/2 mutation carrier, you do not need to retested for mutations that increase breast or ovarian cancer risk – You are already being managed as a high-risk individual for these cancers

What are SNPs? • Single nucleotide polymorphisms

• Minor changes in the genetic code

• Do not seem to completely disrupt the function of the protein

• Any one SNP raises risk only a very tiny amount (for example from 10% to 11%)

• There are now >70 known breast cancer SNP

• It is not known how to combine this information with other risk factors or how to best use this in the clinic

Testing After Cancer Diagnosis • Some individuals undergo genetic testing after they have been diagnosed with cancer • Results of testing may impact cancer treatment • Women with BRCA-related breast cancer have an increased risk of developing a second breast cancer and risk of ovarian cancer • may be particularly effective in BRCA carriers – Platinum based; PARP Inhibitors – In the advanced setting – Studies are underway

PARP Inhibitors • Promising class of therapy for BRCA-related cancers • By inhibiting PARP proteins, damaged DNA within tumor cells is not repaired leading to cell death • Healthy cells are less impacted • Many PARP inhibitor clinical trials exist – OlympiA and OlympiAD • First PARP inhibitor, , approved by FDA less than a year ago for BRCA1/2 carriers with advanced ovarian cancer

OlympiAD Study Assessment of the Efficacy and Safety of Olaparib Monotherapy Versus Physicians Choice in the Treatment of Patients With Germline BRCA1/2 Mutations

• Comparing the PARP inhibitor olaparib to traditional chemotherapies in patients with BRCA1/2 mutations and metastatic breast cancer • Phase III study (The drug or treatment is given to large groups of people to confirm its effectiveness and compare it to commonly used treatments.) • More information at clinicaltrials.gov

OlympiA Study Olaparib as Adjuvant Treatment in Patients With Germline BRCA Mutated High Risk HER2 Negative Primary Breast Cancer

• Studying the use of the PARP inhibitor olaparib as in BRCA+ individuals with triple negative breast cancer – Is recurrence less likely in those who received olaparib compared to those who received a placebo? • Large, international Phase III study • More information at clinicaltrials.gov

Current Research • Vaccinations and • Other targeted drugs/therapies for genetic mutations • Preventing PARP Inhibitor resistance in BRCA mutation carriers • Methods for and testing

Additional Information

• Information on cancer risk evaluation and assistance finding a genetics specialist • Genetic testing education • Basser research registry • Referrals to support organizations • Basser Center events and webinars • BRCAbeat (e-newsletter) www.basser.org [email protected] 215-662-2748 /BasserBRCA