Update on BRCA testing thresholds NICE guidance changes D Gareth R Evans Christie and St Mary s Hospital Manchester UK London July 2014
Guideline Development Group Familial Breast Cancer Any woman with a family history of breast cancer Now INCLUDES affected women Includes those identified in Primary and secondary care
Risk assessment Manual approach with modified Claus Tyrer Cuzick BOADICEA
Genetic testing Family history and carrier probability When available in secondary care, use a carrier probability calculation method with demonstrated acceptable performance (calibration and discrimination) as well as family history to determine who should be offered referral to a specialist genetic clinic. Examples of acceptable methods include BOADICEA1 and the Manchester scoring system. [new 2013]
NICE FBC High Risk (tertiary care) Genetic testing Offer testing if >10% chance of BRCA1/2 or TP53 mutation in family Start with testing an affected family member Must offer full mutation testing-not partial By 2005/6 DH target of 8 weeks per gene Can now offer to an unaffected individual if no affected relative available
NICE genetic testing affected BC Offer people eligible for referral to a specialist genetics clinic a choice of accessing genetic testing during initial management or at any time thereafter. [new 2013] Offer fast-track genetic testing (within 4 weeks of a diagnosis of breast cancer) only as part of a clinical trial. [new 2013] Discuss the individual needs of the person with the specialist genetics team as part of the multidisciplinary approach to care. [new 2013] All requests for fast track testing to be discussed with a consultant in cancer genetics and then, if appropriate, with the laboratory. This will generally only be relevant if a woman is having neoadjuvant chemo (ie chemo before surgery) and the result may help inform treatment decisions
Scoring systems Manual /ballpark-use BCLC data Manchester Scoring Myriad tables (Frank JCO; 1998, 2002) Couch model BRCAPRO Cyrillic BOADICEA only available online
BRCA1 scoring system 5 points MBC (if BRCA1 screened) 8 points Ovary <60 yrs 5 points Ovary >59 yrs 6 points FBC <30 4 points 30-39; 3 points 40-49 2 points 50-59; 1 point 60+
Assessment of score at 20% level (Evans et al 2005) Combined score numbers 0-9 0/62 0% 10-14 10/346 3.5% 16-19 37/265 17% 20-24 40/195 21% 25-29 36/145 28% 30-39 56/112 50% 40+ 51/61 85% Total 230/1200 19% percentage
Modified Manchester score BRCA1 BRCA2 Her2+ -4 0 Lobular -2 0 DCIS only (no -2 0 invasive cancer) LCIS only -3 0 Grade 1 IDC -2 0 Grade 2 IDC 0 0 Grade 3 IDC +2 0 ER pos -1 0 ER neg +1 0 Grade 3 triple neg +4 0
Assessment of Manchester score at 10% level (update 2014) Combined, Ovarian 40+ 83/105 (81%) Male breast All families 10/12 (83%) 104/143(73%) 68/79 (86%) 35-39 32/55 (59%) 6/11 (55%) 56/96 (58%) 30-34 39/90 (43%) 8/12 (67%) 79/170 (47%) 25-29 58/170 (30%) 3/15 (20%) 107/338 (32%) 20-24 47/180 (26%) 4/16 (25%) 119/512 (23%) 15-19 20/147 (14%) 2/26 (8%) 66/709 (9%) 12-14 2/47 (4%) 0/10 (0%) 24/515 (5%) <12 1/25 (4%) 0/4 12/565 (2%) Total 282/830 (35%) 33/106 (32%) 567/3060 (19%)
Sensitivity, ROC Curve 1.0 Source of the Curve Unadjusted combined score for BRCA1/2 0.8 Adjusted combined score for BRCA1/2 Reference Line 0.6 0.4 C statistic 0.74:0.78 0.2 0.0 0.0 0.2 0.4 0.6 0.8 1.0 1 - Specificity Diagonal segments are produced by ties. ROC curve with path adjusted score at 20% combined
Assessment of score at 10% BRCA1 level (Grade 3 TNT) BRCA1 score numbers BRCA1 BRCA2 7 1/8 0/8 1/8 7-9 6/39 (15%) 3/40 (7%) 3/40 (7%) 10-11 12/67 (18%) 9/67 (13.5%) 3/67 (4.5%) 12-13 16/42 (39%) 12/42 (29%) 4/42 (10%) 14-15 15/27 (56%) 14/27 (52%) 1/27 (4%) 16-19 30/49 (61%) 23/49 (47%) 7/49 (14%) 20+ 37/41 (92%) 33/41 (82%) 4/41 (10%) Total 116/266 (43%) 94/266 (35%) 22/266 (8%)
Assessment of score at 10% BRCA1 level (Grade 3 TNT) combined score numbers BRCA1 BRCA2 <10 0 0 0 10-14 4/54 (7.5%) 3/54 (5.5%) 1/54 (2%) 15-19 14/78 (18%) 11/78 (14%) 3/78 (4%) 20-24 28/66 (42%) 22/68 (32%) 6/68 (9%) 25-29 25/48 (53%) 18/48 (38%) 7/48 (15%) 30-39 33/43 (77%) 28/43 (65%) 5/43 (12%) 40+ 23/24 (96%) 20/24 (83%) 3/24 (13%) Total 127/313(41%) 102/313 (33%) 25/313 (8%)
Study Countr y Age and selection Number tested BRCA1 BRCA2 Combined BRCA1/2 POSH UK <41 sporadic Manchester UK <31 unselected FBCS UK <50 mixture 43 5 (11.3%) 0 5 (11.6%) 30 11 (37%) 0 11(37%) 169 37 (22%) 0 11(37%) Gonzalez- Angulo USA unselected 77 11 (14%) 3 (4%) 14 (18%) Young Canada <41 little or no family history 54 5 (9%) 1 (2%) 6 (11%) Comen USA Unselected Ashkenazi Jewish 64 19 (30%) 6 (9%) 25 (39%)
Manchester POSH combined updated Cases Number BRCA1 BRCA2 isolated TNBCs aged 20-30 28 3 (11%) 1 isolated TNBCs aged 31-40 44 5 (11%) 0
High grade serous ovarian cancer 1,001 Women with nonmucinous OC 16.6% of serous cancer patients (highgrade serous, 22.6%) diagnosed 61+ with no PSFH, 16/250 (6.4%) Alsop et al JCO 2012
number BRCA1/2 neg % BRCA1/2 pos % 40 45 35 77.8 7 15.6 41-50 153 105 68.6 37 24.2 51-60 346 254 73.4 59 17.1 61 457 383 83.8 38 8.3 Pos FH 194 105 54.1 75 38.7 No FH 749 625 83.4 62 8.3 Serous 709 536 75.6 118 16.6 Clear cell 63 52 82.5 4 6.3 Endometrioid 119 98 82.4 10 8.4
TNT >40 What about TNT 40-50? Robertson (FBCS) et al BJC 2012 suggested testing all <50 4/38 with pathology unadjusted MS <15 Detection rate not clear in sporadics >50 detection rate low only 4/101 (4%) unselected
What can all be tested TNBC <40 years High grade serous Ovarian <60 years
Do these criteria meet the 10% threshold? 1. Bilateral breast cancer and both cancers diagnosed <40 years -OK MS16+ 2. Triple negative breast cancer diagnosed <50 years -Evidence for sporadic 40-50 lacking 3. Non- mucinous Epithelial ovarian cancer evidence for sporadic >60 well below 10% 4. Bilateral breast cancer and a relative diagnosed with breast cancer <60 years MS as low as 8! 4/78 5. A first degree relative with breast cancer and both diagnosed <40 years OK MS16+ 6. A first degree relative with a non-mucinous epithelial ovarian cancer -MS as low as 12! -1/16 7. A family history with a Manchester score greater than or equal to 15