Understanding BRCA1/2 Cancer Risk

Editor's Notes

• #5: coalition of patients, physicians and health care groups to challenge Myriad’s patents directed at BRCA1 and BRCA2 genes. As alleged in that lawsuit, Myriad maintained a monopoly over diagnostic testing of BRCA1 and BRCA2 genes under the Myriad patents and threatened legal actions against entities that wished to provide BRCA1 and BRCA2 gene testing to women. Following a multi-year legal battle, the unanimous Supreme Court decision held that genomic sequences, whether isolated or not, may not be patented and declared invalid the Myriad BRCA1 and BRCA2 patent claims challenged in that suit
• #6: SHOW OF HANDS….HOW MANY OF YOU ARE FOLLOWING PATIENTS WITH A HBOC.
• #7: Exploited genes/ pathways to escape normal cell growth/ cell death rules : TSG—DNA repair genes; Oncogenes: Oncogenes are mutant forms of normal functional genes termed proto-oncogenesis that play a role in normal cell proliferation.
• #8: DNA is found inside a special area of the cell called the nucleus. Because the cell is very small, and because organisms have many DNA molecules per cell, each DNA molecule must be tightly packaged. This packaged form of the DNA is called a chromosome.Transcription is the process of converting the genetic information stored in DNA to messenger RNA (mRNA). This is performed by RNA Polymerase in the nucleus of the cell (assuming the organism is eukaryotic). At this point the mRNA is comprised of exons and introns, (i.e. expressed regions and non-expressed regions) and the introns are cut out with splicing machinery. Now the mRNA is exported from the nucleus into the cytoplasm where it meets the ribosome. The ribosome uses the information stored in the mRNA, along with transfer RNAs (tRNA) holding onto amino acids to create protein. This process is known as translation because you are translating from the language of nucleotides to the language of amino acids.
• #9: 23 pairs of chromosomes: 22 pairs of numbered chromosomes; 1 pair of sex chromosomes: X and Y  male
• #10: DNA is made of chemical building blocks called nucleotidesbiological instructions are contained in a strand of DNA.
• #16: When possible, always test the affected family member, rather than someone who hasn’t had cancerGenetic testing rarely gives a black & white “yes/no” answer
• #18: FA: rare autosomal recessive disease, characterized by multiple congenital anomalies, progressive bone marrow failure, acute leukemia and cancer susceptibility.The FA assocaitedgene products along w/ BRCA1and BRCA2 have been found to function in a common pathway that regulates cellular response to DNA damageDisease characteristics. Fanconi anemia (FA) is characterized by physical abnormalities, bone marrow failure, and increased risk of malignancy. Physical abnormalities, present in 60%-75% of affected individuals, include one or more of the following: short stature; abnormal skin pigmentation; malformations of the thumbs, forearms, skeletal system, eyes, kidneys and urinary tract, ears (and decreased hearing), heart, gastrointestinal system, central nervous system; hypogonadism; and developmental delay. Progressive bone marrow failure with pancytopenia typically presents in the first decade, often initially with thrombocytopenia or leukopenia. By age 40 to 50 years, the estimated cumulative incidence of bone marrow failure is 90%; the incidence of hematologic malignancies (primarily acute myeloid leukemia) 10%-30%; and of nonhematologic malignancies (solid tumors, particularly of the head and neck, skin, GI tract, and genital tract) 25%-30%. Diagnosis/testing. The diagnosis of FA rests upon the detection of chromosomal aberrations (breaks, rearrangements, radials, exchanges) in cells after culture with a DNA interstrand cross-linking agent such as diepoxybutane (DEB) or mitomycin C (MMC). Molecular genetic testing is complicated by the presence of at least 15 genes, which are responsible for the known FA complementation groupsCells lacking BRCA2 are deficient in the repair of double-strand DNA breaks, as reflected in a hypersensitivity to ionizing radiation
• #19: Just to clarify these are not eligibility criteria for testing (which Claire will present) but rather features that should raise suspicion for HBOC. Papillary serous carcinomatosis of the peritoneum TNBC: Kwon, JS et al. JCO 2010;28: 4214-4240” cFoulkes WD Clin Cancer Res 2004:10;2029-34BRCA1 tumors likely than sporadic tumors to be estrogen receptor-negative and progesterone receptor-negative, and are less likely to demonstrate HER2/neu overexpression; thus, BRCA1-related tumors fall within the category of “triple negative” breast cancer% ER+ Breast Cancers in BRCA1/2 Carriers by Age at DiagnosisEstrogen Receptor Negative in BRCA 1 carriersBRCA1 carries <45 yo, 19% ER+, 55-65: 38% ER+ cancersBRCA2 carriers across all age groups: 71-80% ER+ cancers
• #20: Situations that may lower the threshold of suspicion for HBOC include the following:Families with a limited family structure, defined as having fewer than two first- or second-degree female relatives surviving beyond the age of 45 years in either lineage, as this may lead to an underrepresentation of female cancers despite the presence of a predisposing family mutationOophorectomy at a young age in family members, which reduces the risk for both breast and ovarian cancer, as this could mask a hereditary susceptibility to both breast and ovarian cancer Presence of adoption in the lineage Populations at risk of having a BRCA1 or BRCA2mutation (e.g., Ashkenazi Jewish descent)
• #21: This may result from a founder effect, which occurs when a population undergoes rapid shrinkage and then expansion in an isolated setting. In a population that is geographically or reproductively isolated, an individual called a founder carries or develops a germline mutation that is rare in the general population. Because of reproductive isolation, later generations of an isolated population will have a higher frequency of a mutation than the original population. Today, one percent of the Ashkenazi Jewish population--one person in 40--carries a 185delAG mutation in BRCA1, which places them at higher than the average risk for breast and ovarian cancer.COH Jeff Weitzel is BRCA 1185delAG is also prevalent in Latinos. 10% true positive Latinos. Other populations with known founder mutations: Icelandic, British, Dutch, Chinese, Russian, African American, Hispanic, “Mexican Founder Mutation”—Large deletion seen and speculated to have Amerindian/Mestizo originFrank TS, Deffenbaugh AM, Reid JE, et al. Clinical characteristics of individuals with germline mutations in BRCA1 and BRCA2: analysis of 10,000 individuals. J Clin Oncol. 2002;20:1480-1490.Struewing JP, Hartge P, Wacholder S, et al. The risk of cancer associated with specific mutations of BRCA1 and BRCA2 among Ashkenazi Jews. N Engl J Med. 1997;336:1401-1408.
• #22: Frank TS, Deffenbaugh AM, Reid JE, Hulick M, Ward BE, Lingenfelter B, Gumpper KL, Scholl T, Tavtigian SV, Pruss DR, Critchfield GC. Clinical characteristics of individuals with germline mutations in BRCA1 and BRCA2: analysis of 10,000 individuals. J Clin Oncol. 2002;20:1480–90. [PubMed: 11896095] 3 founder mutations account for 97.5% of BRCA positive patients that indicated AJ ancestry; 2.5% due to mutations in the BRCA1 and 2 (roughly 50/50)Study >3000 individual of AJ ancestry; 20%; 600 had alterations; In the Western/Northern European group, 9.7% of mutations in high-risk patients were large rearrangements vs. 5.9% in the elective group. Large rearrangements are a significant contributor to the overall spectrum of mutations, and show ethnic-specific variation in their contribution to the BRCA1 and BRCA2 mutation profile. Among Latin American/Caribbean patients, large rearrangements accounted for 20.6% of mutations in the high-risk group and 12.8% in the elective group, indicating more large rearrangements in this ethnic group overall (p<<0.001, p=0.02). Judkins et al. 2012
• #23: RETURN TO THE FA PATHWAY AS it is fertile ground for genes that predispose to breast/ovarian cancer
• #25: Targeted complete genomic sequence of 21 genes82/360 patients with primary ovarian, fallopian, or peritoneal carcinoma had a deleterious mutation in at least one of 12 genesWalsh T et al. PNAS 2011;108:18032-18037360 patients (95% of those who were approached)Primary ovarian, fallopian, peritoneal carcinomaExclusions:Recurrent diseaseCases referred for genetic riskCancers identified at the time or risk-reducing surgery 360 subjects harbored 85 germ-line loss-of-function mutations in 12 genes: 40 (11.1%) in BRCA1, 23 (6.4%) in BRCA2, and 22 (6.1%) in 10 other genes (Fig. 1 and Table S1). Three subjects carried mutations in two genes, so the total proportion of subjects with at least one germ-line mutation was 0.23 (82/360). Features of the mutations and of neoplastic histology, family history, and age of diagnosis for each of the sub- jects with a mutation are provided in Table S2.3 subjects germline mutations in TP53None met criteria for Li-Fraumeni*BARD1, BRIP1, MRE11A, NBN, RAD50, and RAD51C are genes involved in the Fanconi anemia (FA)–BRCA pathway, which is critical for DNA repair by homologous recombination and interact in vivo with BRCA1 and/or BRCA2.3,8-10 Mutations in these genes are estimated to confer up to a 4 fold increase in breast cancer risk, and mutations in each have been reported in at least 1 identified case of ovarian cancer to date.11Panels: negative, 2 families where provided an “answer”: Palb2, ATM mutation deleterious mutations were identified; multiple families where several variants of unknown significance. Variants is found—require a fair amount of follow-up; --cautionary tale due--1. consent process: informed consent each gene and risk associated with each gene are reviewed by our GC--2. analysis of variants--3. low risk patients, diverse ethnic groups more likely to find variants of unknown significance
• #35: Robson M et al N Engl J Med 2007;357:154-162; breast and ovarian cancer risks for women with BRCA mutations broken down by 10 year intervalsLinear risk of developing ovarian cancer – less affected by age. Up to age 70 yr. SNPs that modify risk of sporadic breast cancer also modify risks in BRCA1 and BRCA2(Antonio AC et al. Nature Genetics 2010;42:885-92; Gaudet MM PLoS Genetics 2010;6(10):e1001183 )Age specific cumulative breast cancer risks for BRCA2 mutation carrier by percentiles of combined genotype distribution at SNPs –single nucleotide polymorphisms in different genes SNPS in FGFR2, TOX3/TNRC9,MAP3K1, LSP1, 2q35, SLC4A7/NEK10, 5P12CIMBA consortium: 6000 BRCA2 mutation carriers>9000 BRCA1 mutation carriersCompare 40 years old No breast cancer vs.<40 affected by breast cancerAll from the same cohort of women. Control subjects: 1816; Case: 1816; BRCA1 1405 (77.4%); BRCA2 411 (22.6%)Thompson D et al. AmJHumGenet 2001:68;410; Rebbeck TR et al. Ca Res 2001:61;5420; Brunet J et al. JNCI 1998:90; 761 King MC et al. Science 2004; Rebbeck T et al. NEJM 2002;346:1616-22
• #36: Studies: have suggested that oral contraceptives may increase the risk of breast cancer in mutation carriers. BRCA2 mutation carriers usingoral contraceptives over 4 years had increased risk of breast cancer. Case–control studies examining the effect of oral contraceptives on the risk of ovarian cancer in BRCA mutation carriers have demonstrated a substantially lower risk (up to 60%) in womenwho have had 3 or more years of exposure. Narod SA, Risch H, Moslehi R, et alN Engl J Med 1998;.339:424-8.McLaughlin JR, Risch HA, Lubinski J,et al. Reproductive risk factors for ovarian cancer in carriers of BRCA1 or BRCA2 mutations: a case-control study. Lancet Oncol 2007;8:26-34.Whittemore 2004: We obtained self-reported lifetime histories of oral contraceptive use from 451 women who carried mutations of BRCA1 or BRCA2. We used conditional logistic regression to estimate the odds ratios associated with oral contraceptive use, comparing the histories of 147 women with ovarian cancer (cases) to those of 304 women without ovarian cancer (controls) who were matched to cases on year of birth, country of residence and gene (BRCA1 vs BRCA2). Reference ages for controls had to exceed the ages at diagnosis of their matched cases. After adjusting for parity, the odds-ratio for ovarian cancer associated with use of oral contraceptives for at least 1 year was 0.85 (95 percent confidence interval, 0.53-1.36). The risk decreased by 5% (1-9%) with each year of use (P for trend=0.01). Use for 6 or more years was associated with an odds-ratio of 0.62 (0.35-1.09). These data support the hypothesis that long-term oral contraceptive use reduces the risk of ovarian cancer among women who carry mutations of BRCA1 or BRCA2.Whittemore; 2004: Among women who carry mutations of BRCA1 or BRCA2, wefound reduced risk associated with use of oral contraceptives andevidence for increasing risk reduction with increasing duration ofuse. The reduction in risk of 14% among ever users and 38%among long-term users are consistent with, but somewhat weakerthan, reductions observed in the general population. In a pooledanalysis of six population-based case–control studies of oralcontraceptives and the risk of ovarian cancer in the US, the riskreduction associated with ever use was 34%, and that associatedwith 6 or more years of use was 70%
• #39: Moderately Increased Risk : everything in between. Gail model:Claus model:Tyler Kusick90%Bilateral mastectomy>90% Removal ovaries & fallopian tubes model:Gail et al.2 provide risk of breast cancer by agiven age†‡Age, family history of breast cancer (FDR),reproductive factors, number of breastbiopsies,personal history of atypia§Does not include breast cancer in non-FDRor family history of ovarian cancer; derivedfrom a population undergoing screeningClaus et al.3 provide 5-year and lifetimeprobability of breast cancer‡Age, family history of breast cancer (FDR,SDR)Does not include risk factors other than familyhistory or family history of ovarian cancer; incompletevalidation in nonwhite populationsTyrer–Cuzick (Tyrer et al.4) provides 10-yearand lifetime probability of breast cancer¶Age, family history of breast and ovariancancer;Ashkenazi ethnic background,reproductivefactors, morphometric factors(height, weight), personal history of atypia,lobular carcinoma in situIncomplete validation, especially in nonwhitepopulationsBRCAPRO (Berry et al.5) provides age-specificprobability of breast cancer‡‖Age, family history of breast and ovariancancer,Ashkenazi ethnic backgroundDoes not include risk factors other than familyhistory; incomplete validation in nonwhitepopulations
• #40: Some new evidence that mammograms at LESS THAN AGE 30 in BRCA carriers may increase risk for breast cancer. 2nd study:Retrospective cohort study 1993 female carriers of BRCA1/2 mutations in UK, France, Netherlands,  any exposure to diagnostic radiation before age 30 was associated w/ an increased risk of breast cancer HR 1.9 with a dose response pattern. Increasing risk w/ increasing number of radiographs before age 20 and age 30. MRI Alone: Methods We did a prospective multicentre cohort study in 649 women aged 35–49 years with a strong family historyof breast cancer or a high probability of a BRCA1, BRCA2, or TP53 mutation. We recruited participants from 22centres in the UK, and offered the women annual screening with CE MRI and mammography for 2–7 years.Findings We diagnosed 35 cancers in the 649 women screened with both mammography and CE MRI (1881 screens):19 by CE MRI only, six by mammography only, and eight by both, with two interval cases. Sensitivity wassignificantly higher for CE MRI (77%, 95% CI 60–90) than for mammography (40%, 24–58; p=0·01), and was 94%(81–99) when both methods were used. Specificity was 93% (92–95) for mammography, 81% (80–83) for CE MRI(p0·0001), and 77% (75–79) with both methods. The difference between CE MRI and mammography sensitivitieswas particularly pronounced in BRCA1 carriers (13 cancers; 92% vs 23%, p=0·004).MARIBS (2005): 120 MUTATION CARRIERS; 12 with invasive cancers2nd study:Retrospective cohort study 1993 female carriers of BRCA1/2 mutations in UK, France, Netherlands,  any exposure to diagnostic radiation before age 30 was associated w/ an increased risk of breast cancer HR 1.9 with a dose response pattern. Increasing risk w/ increasing number of radiographs before age 20 and age 30.
• #41: N= 483 – 105 underwent b/l prophylactic mastectomy; 378 controls HR: 0.05 F/U 7.5 Rebbeck 2004Mean age at time of surgery for the wholesample was 38.1 years. Follow-up of controls began at amean age of 36.3 years. Postsurgery follow-up duration was5.5 years in cases and 6.7 years in controls. Of the 105mutation carriers with bilateral prophylactic mastectomy(cases) in the total cohort, two (1.9%) were diagnosed withbreast cancer after bilateral prophylactic mastectomy (bothsubcutaneous) compared with 184 (48.7%) of 378 controls.Pathology records of the two women with postbilateralprophylactic mastectomy breast cancer indicated no detectableevidence of breast cancer at the time of prophylacticsurgery. These breast cancers occurred 2.3 and 9.2 yearsafter bilateral prophylactic mastectomy. Figure 1 presents aKaplan-Meier analysis of breast cancer events by postsurgeryfollow-up time in cases compared with controls.BPM reduced the risk of breast cancer by approximately 95% in women w/ prior or concurrent RR BSO and by approx 90% in women w/ intact ovaries; mean age 38 years old
• #42: New techniques: DIEP/SGAP flaps; 1-step implant w/ alloderm, OtherSentinel lymph node? (<5% occult primary rate) :and Superficial Inferior Epigastric Artery (SIEA) flaps recreate new breasts with your own abdominal skin and fat, while the and Inferior Gluteal Artery Perforator (IGAP) flaps use skin and fat from the buttocks. Risk-reducing mastectomy (RRM) reduces the risk of breast cancer by at least 90% in mutation carriers.62 The cosmetic effect of the procedure may be mitigated by newer reconstructive techniques,Skin-sparing mastectomy seems to be an oncologically safe technique and does not increase in particular the risk of local, regional or systemic recurrences. It facilitates immediate breast reconstruction using implants or myocutaneous flaps, resulting in excellent cosmesis and high level of patient satisfaction.
• #43: Preventive mastectomies are done most often on women in their 30s and 40s, but women at both ends of the age spectrum also have this surgery. In some cases, the decision to have this surgery depends on when a woman discovered her hereditary risk. In other cases, something in a woman's recent experience may have altered how she feels about having this surgery.
• #44: Risk-reducing salpingo-oophorectomy (RRSO) is an important preventive intervention in BRCA mutation carriers. Although this surgery has not beenevaluated in randomized trials, retrospective and prospective cohort studies indicate a reduction in the risk of BRCA-associated gynecologic cancerFound 85% reduction in BRCA1 ass’d gynecological cancer riskSurgery does not eliminate the risk of gynecologic cancer; the residual risk for primary peritoneal cancer after prophylactic surgery has been estimated to be between 2 and 4% and may reflect the propensity of the peritoneal tissue to undergo malignant transformation [31,35,36]. This risk for cancer may also result from untreated occult microscopic tubal or ovarian disease, which presents as primary peritoneal cancer following surgery. • BRCA1-positive woman with breasts intact, no previous breast cancer: – HRT (combined estrogen and progesterone for women with salpingo-oophorectomy only, estrogen alone for women with hysterectomy and salpingo-oophorectomy) may be offered after prophylactic salpingo-oophorectomy to the age of natural menopause (age 50–52 years); – There is insufficient evidence to determine the safety of androgen replacement therapy after salpingo-oophorectomy in BRCA-positive women; – If taking tamoxifen or raloxifene, for osteoporosis prevention or for reduction of breast cancer risk, HRT should not be prescribed. • BRCA2-positive woman with breasts intact, no previous breast cancer: – HRT (combined estrogen and progesterone for women with salpingo-oophorectomy only, estrogen alone for women with hysterectomy and salpingo-oophorectomy) may be considered after prophylactic salpingo-oophorectomy. There is limited data regarding the safety of hormone replacement in women who are BRCA2-positive; – There is insufficient evidence to determine the safety of androgen replacement therapy after salpingo-oophorectomy in BRCA-positive women; – If taking tamoxifen or raloxifene, for osteoporosis prevention or for reduction of breast cancer risk, HRT should not be prescribed. • BRCA-positive woman with prior breast cancer: – Systemic HRT is generally contraindicated for women with a previous diagnosis of breast cancer. Local vaginal estrogens may be considered; – Consider selective serotonin reuptake inhibitors or selective serotonin-norepinephrine reuptake inhibitors for the management of vasomotor symptoms. • BRCA-positive woman with prophylactic mastectomy, no previous breast cancer: – HRT (combined estrogen and progesterone for women with salpingo-oophorectomy only, estrogen alone for women with hysterectomy and salpingo-oophorectomy) should be offered after prophylactic salpingo-oophorectomy to the age of natural menopause; – Androgen replacement therapy may be considered with discussion of possible side effects.
• #45: and a reductionRRSO was with significant protection again BRCA1-associated gynecologic cancer and BRCA-2 associate breast cancer; 72% in the risk of breast cancer of approximately 50%, most likely through the induction of premature menopause.