Predictive and Diagnostic Testing for Cancer in Women. Aparna Rajadhyaksha MD

Transcription

1 Predictive and Diagnostic Testing for Cancer in Women Aparna Rajadhyaksha MD

2 Hereditary Cancer s in Women BRCA1 &2 Other Breast Cancer Genes Li Fraumeni PTEN CHEK2

3 BRCA1&2 t BRCA1 is part of a complex that repairs double-strand breaks in DNA BRCA1& BRCA2 proteins interact with RAD51 during repair of DNA double-strand breaks. These three proteins play a role in maintaining the stability of the human genome

4 Prevalence Hereditary breast and ovarian cancer (HBOC) resulting from mutations in BRCA1 and BRCA2 is the most common form of both hereditary breast and ovarian cancers Occurs in all ethnic and racial populations. Prevalence of BRCA1/2 mutations :1:400 to 1:800 Ford et al 1994, Claus et al 1996, Whittemore et al 1997

5 Clinical Diagnosis:If >1of the following features are present in a family 1. Early-age-onset (age <50 years) breast cancer including invasive and in situ (DCIS) breast cancers. 2a. 2 breast primaries OR breast +ovarian/fallopian tube/primary peritoneal cancer in a single individual OR 2b.>2breast primaries OR breast + ovarian/fallopian tube/primary peritoneal cancers in close relatives(s) from the same side of the family. 3. Populations at risk (e.g., Ashkenazi Jewish). 4. Member of a family with a known BRCA1 or BRCA2 mutation. 5. Any male breast cancer. 6. Ovarian/fallopian tube/primary peritoneal cancer at any age. National Comprehensive Cancer Network 2010

6 Situations that may lower the threshold of suspicion for HBOC Families with a limited family structure Oophorectomy at a young age in family members (reduces the risk) Presence of adoption in the lineage Populations at risk of having a BRCA1 or BRCA2 mutation

7 BCAPRO Myriad II Manchester Scoring System Probability Tables HugeriskApps: Harvard

8 BRCA1 and BRCA2 mutation frequencies in individuals of Ashkenazi Jewish ancestry

9 BRCA1/2 Incidence in Indian Population Sr. Study No. 1 Our Data (Samples outsourced to RLS) 2 Juwle et al Med Oncol, 2012 (Reliance Data) 3 BC Das Breast Cancer Res Treat Nov;88(2): Vaidyanathan J. Biosci. 34(3), September 2009, , 5 Hansa et al. Asian Pacific J Cancer Prev, 13 (11), No. of BRCA1/2 BRCA1 BRCA2 Samples Mutations Mutations Mutations 9 Cases (Br Ca Patients) 51 (Patients Relatives) 24 Familial BrCa 100 Sporadic Br Ca 61 Familial Breast/ Ovarian Ca 32 (3 mutations in BRCA1 were studied) 26/50 17 (34%) 12 (24%) (52%) 29/51 (57%) 24 (47%) 6 (12%) 6 (25%) 6 (25%) /61 (28%) 15 (24.6%) 2 (3.28%) NA 13 (40.62%) NA

10 Testing for BRCA1 &2 Targeted Mutation Analysis: Ethnic specific Sequence analysis: Sequence Variants Deletion/Duplication Analysis: Exonic or multiexonic deletion; complex alleles

11 Interpretation of Results Mutation is Absent: Targeted vs. Sequence Analysis Mutation is Present Inconclusive: Variant of Unclear Significance 10-15%

12 Estimated Frequencies for Mutation Detection in BRCA1 &2

13 Family not known to have a BRCA1 or BRCA2 germline mutation More informative testing if affected person is tested Especially if the breast cancer occurred at an earlier age (i.e., <50 years). If the affected relative is unavailable, testing for a germline mutation may be performed on individuals without a cancer history with the understanding that failure to detect a mutation does not eliminate the possibility of a BRCA1 or BRCA2 germline mutation being present in the family.

14 Breast Cancer Pathology Excess of medullary histopathology, Higher histologic grade, More likely to be ER ve and PR -ve, HER2/neu overexpression; BRCA1-related tumors triple negative breast cancer Higher frequency of TP53 mutations is observed in BRCA1-related tumors Overexpress p27 & Cyclin E1 Emerging data suggest that BRCA1-related breast cancers are more likely to be derived from the basal epithelial layer of cells of the mammary gland, cells thought to represent the breast stem cells Foulkes et al 2003, Foulkes et al 2004, Lacroix & Leclercq 2005, Lakhani et al 2005, Atchley et al 2008

15 The Breast Cancer Linkage Consortium (1997).

16 Ovarian Cancer Pathology Serous adenocarcinomas Higher grade More frequently bilateral P53 positive Human Patholy 2004

17 Contribution of BRCA1 &2 to Ovarian Cancer- Ramus et al Families with BRCA1 (blue), BRCA2 (red) and no detectable mutation (yellow). (a) Families with mutations with increasing number of ovarian cancer cases i) 2 ovarian cancer cases only, ii) 3 or more ovarian cancer cases only. (b) Families with mutations with increasing number of breast cancer cases i) 2 or more ovary and no breast cancer, ii) 2 or more ovary and one breast cancer case, iii) 2 or more ovary and 2 or more breast cancer cases.

18 Genotype/Phenotype Correlation Cancer risks may differ by gene and also by location of a mutation within the gene. Mutation in the ovarian cancer cluster region (OCCR) of exon 11 of BRCA2 have a Ov CA> Br CA than elsewhere in the gene BRCA2 mutation positive: Families of Polish ancestry less pancreatic cancer than other ethnicities LIGHT BLUE: OVARIAN CANCER DARK BLUE: BREAST CANCER A: BRCA1 B: BRCA2 [Lubinski et al 2004].

19 Penetrance Unexplained: Some individuals with mutation may have multiple primary cancers <50 years, while others with the same mutation may develop cancer only after age 70 years, or not at all. "Multiple-breast case families: Variable risks 40% to 60% range and penetrance No associated benign tumors or physical abnormalities are presently known to be associated with BRCA1/2 mutations Levy-Lahad et al 2001, Antoniou et al 2008, Hopper et al 1999

20 PENETRANCE

21 Summary of cancer risks with mutations in BRCA1 Chen et al 2006: Risk of developing cancer by age 70 years : - Breast Cancer 57% - Ovarian Cancer of 40% Metcalfe et al 2004: The contralateral breast cancer risk for a BRCA1 mutation is 27% within five years of the initial breast cancer diagnosis

22 Other Cancer Related Risks Fallopian tube carcinoma: Fimbria 120 RR Primary papillary serous carcinoma of the peritoneum 4% at 20 yrs following oophorectomy- indistinguishable from serous adenocarcinoma of ovaries Uterine body:2.6 Cervix:3.7 (age <65 years) Prostate Cancer: 1.8 Pancreatic Cancer 1.2 % Male Breast Cancer 1.2% Finch et al 2006, Thompson & Easton 2002, Lynch et al 2005, Tai et al 2007

23 BRCA2 Cancer Risk Chen & Parmigiani 2007: Risk of developing cancer by 70 years: - Breast Cancer : 49% - Ovarian cancer :18% Risk for ovarian cancer lower than BRCA1:1.4% Risch et al 2001: Ovarian cancer in BRCA2 is more likely to occur >50 years than BRCA1. Metcalfe et al 2004: The contralateral breast cancer risk in BRCA2 is 12% within 5 years of the initial breast cancer diagnosis.

24 BRCA2 Other Related Cancer Risks Fallopian tube carcinoma less frequent than BRCA1 :BRCA2>BRCA1:Male breast cancer (6% by 70 yrs) Prostate Ca in males 4.6, younger age of onset Pancreatic Ca 3.5 indicator of BRCA2 mutation Gallbladder:5.0 Bile Duct& stomach:2.6 Casey et al 2005, Fentiman et al 2006, Tryggvadottir et al 2007, Petersen & Hruban 2003, Van Asperen et al 2005

25 Prognosis Breast CA Variable in other populations Ashkenazi Jewish Population: a. Higher rates of contralateral breast cancer and ipsilateral breast cancers in women treated conservatively. b. Increased rate of ipsilateral breast cancers was only seen BRCA1 or BRCA2 mutation not undergone prophylactic oophorectomy c. The increase in second primary cancers reported in these studies has not translated into significant differences in survival. Pierce et al 2006

26 Ovarian CA Prognosis Better median survival 53.7 months vs months & 5 year survival rates 38.1% vs 24.5%;) with an Ashkenazi founder mutation Greater survival benefit among those who were BRCA2 > BRCA1 mutation positive. Increased in vitro sensitivity to platinum-based drugs in BRCA1 mutant cells. Chetrit et al 2008, Pal et al 2007, Byrd et al 2008, Lafarge et al 2001, Quinn et al 2003

27 Management Prophylactic Mastectomy : 90% reduction in Breast CA Prophylactic BSO:80%-96% risk reduction in ovarian cancer Following oophorectomy the peritoneum remains at risk for primary peritoneal cancer: 2% 53% risk reduction for breast cancer in women undergoing bilateral prophylactic oophorectomy BRCA2 mutation >BRCA1 mutation. Kauff et al 2008

28 Management Chemotherapy: Tamoxifen a. ER Positive Tumors: BRCA2> BRCA1= 62% b. BRCA1 &2: 50% reduction in the risk of developing contralateral breast cancer c. Adverse consequences: higher rates of endometrial cancer and thromboembolic episodes (including pulmonary embolism Breast feeding. BRCA1 mutation who breast-fed for a cumulative total of more than one year had a statistically significant reduced risk for breast cancer. King et al 2001, Narod et al 2000, Jernstrom et al 2004

29 PARP-1 Inhibitors

30 Surveillance Breast cancer screening guidelines include: Monthly breast self-examination starting in early adulthood Semiannual clinical breast examination beginning at age 25 years Annual mammography and breast MRI beginning at age years Ovarian CA: Transvaginal US and CA 125 Screening should be individualized based on the earliest age of onset in the family.

31 BRCAX BRIP Li Fraumeni PTEN Diffuse Gastric Carcinoma CHEK2 Differential Diagnosis Others: ATM, NLK, NBS1, RAD 50, PALB2, BARD1 Association with 2-4 fold increased risk for breast cancer Mutations more frequent in younger onset cases, but figures uncertain Account for 2-4% of familial breast cancers Unclear benefit of genetic testing

32 FANCONI s ANEMIA AND BREAST CA

33 FANCONI N/PALB2 The gene PALB2 is a tumor suppressor gene that has been identified as a pancreatic cancer susceptibility gene. It interacts with BRCA2 to repair damaged DNA and help maintain the rate of cell growth and division. Breast Cancer: PALB2 mutations may be associated with a two-fold increase in breast cancer susceptibility.

34 Early Breast Cancer: BRIP1 associated BRCA1-interacting protein 1 (BRIP1; FANCJ/BACH1), interacts with BRCA1 BRIP1 was recently identified as deficient in Fanconi anemia (FA) complementation group J. Increased risk of Breast Cancer 2%

35 Li- Fraumeni Syndrome Cancer predisposition syndrome Soft-tissue sarcoma, breast cancer, leukemia, osteosarcoma, melanoma, and cancer of the colon, pancreas, adrenal cortex, and brain. LFS is diagnosed in individuals meeting established clinical criteria. More than 50% of individuals diagnosed clinically have an identifiable disease-causing mutation in TP53. The risk of developing breast cancer in an individual with a germline mutation in TP53 is approximately 49% by age 44 years and 60% overall. Inheritance is autosomal dominant.

36 PTEN Cowden syndrome (CS): Multiple hamartoma syndrome High risk for benign and malignant tumors of the thyroid, breast, and endometrium. The lifetime risk breast cancer is 25%-50%, with an average age of diagnosis years. The lifetime risk for thyroid cancer (usually follicular, rarely papillary, but never medullary thyroid cancer) is around 10%. The risk for endometrial cancer may approach 5%-10%. The diagnosis of PHTS is only made when a PTEN mutation is identified. Inheritance is autosomal dominant.

37 Hereditary diffuse gastric cancer (HDGC) Autosomal Dominant susceptibility for diffuse gastric cancer. Gene causing it is CDH1 Diffuse gastric cancer is also referred to as signet ring carcinoma or isolated cell type carcinoma. The average age of onset of hereditary diffuse gastric cancer is 38 years (range: age years). The majority of the cancers in individuals with CDH1 mutations occur before age 40 years. The estimated cumulative risk for gastric cancer by age 80 years is 67% for men and 83% for women. Women also have a 39% risk for lobular breast cancer.

38 CHEK2 The CHEK2 variant c.1100delc (NM_ ) 2-3X increase in breast cancer risk in women and a tenfold increase of risk in men. Stronger association among families with early-onset breast cancer Increased risks for thyroid, prostate, colon, and kidney cancer among individuals with one of the three CHEK2 founder alleles: c.1100delc, c.319+1g>a(ivs2+1g>a), and p.ile157thr (NM_ ) []. CHEK2 Breast Cancer Case Control Consortium 2004, Bernstein et al 2006, Weischer et al 2007, Cybulski et al 2004

39 It s All Connected

40 Questions? THANK YOU!