Abstract # 1503: Predisposing germline mutations in high grade ER+ HER2- breast cancer patients diagnosed age < 50

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1 Abstract # 1503: Predisposing germline mutations in high grade ER+ HER2- breast cancer patients diagnosed age < 50 Garber JE 1, Tung NM 2, Elkin EP 3, Allen BA 3, Singh NA 3, Wenstrup R 3, Hartman AR 3, Winer EP 1, Lin NU 1 1 Dana-Farber Cancer Institute, Boston, MA; 2 Beth Israel-Deaconess Medical Center, Boston, MA; 3 Myriad Genetics, Inc., Salt Lake City, UT

2 Study Rationale Platinums and PARP inhibitors (PARPi) are being studied in women with triple negative breast cancer (TNBC), especially BRCA1/2 mutation carriers. Early PARPi data showed activity in women with BRCA1/2 ER+ tumors as well. The frequency of germline BRCA1/2 mutations in women with TNBC is 25% when diagnosed 50 and 10% 60.

3 Study Rationale - 2 Epidemiologic data show higher grade ER+ tumors in BRCA1/2 mutation carriers diagnosed age 50. NCCN guidelines recommend genetic testing of women diagnosed age 45. We wondered whether we are missing patients who might benefit from targeted therapies by considering only TNBC. We looked beyond BRCA1/2 to begin to contribute to that epidemiology.

4 Methods Blood specimens from consented invasive breast cancer patients from the Dana-Farber Cancer Institute SPORE in Breast Cancer biobank who met the following criteria: Age at diagnosis <50 years Estrogen receptor positive HER2 negative Grade III (poorly differentiated) Invasive cancer only 146 consented patients with clinical data including reviewed pathology 20 excluded for grade II 20 excluded without genetic data (insufficient DNA) 106 subjects with specimens available for analysis

5 Methods - 2 DNA mutations in 25 cancer predisposition genes were identified using a next generation sequencing-based panel Germline sequence variations and large rearrangements were classified for pathogenicity 95% confidence intervals were calculated by the Clopper- Pearson method.

6 Deleterious mutations identified in 106 subjects Genes N = # Patients with deleterious mutation (%) 95% Confidence interval Any deleterious mutation 11 (10.4) 5.3, BRCA1 or BRCA2 7 (6.6) 2.70, BRCA1 4 (3.8) 1.04, 9.38 BRCA2* 3 (2.8) 0.59, 8.05 Other genes related to breast cancer 5 (4.7) 1.55, ATM* 2 (1.9) 0.23, 6.65 CHEK2 1 (0.9) 0.02, 5.14 PALB2 2 (1.9) 0.23, 6.65 * One patient had a deleterious mutation in both BRCA2 and ATM

7 Other Genetic Findings 47/106 patients had a VUS in any gene (range 1-4) 39 had VUS only 8 had deleterious mutation and VUS 2 mono-allelic mutyh mutations were not included in the table

8 Deleterious mutation by demographic and clinical characteristics Characteristic No Mutation N (%) Mutation N (%) Total P value Ashkenazi Jewish Ethnicity No 89 (93.7) 8 (72.7) 0.02 Yes 6 (63) 3 (27.3) PR status Negative 5 (5.3) 3 (27.3) < 0.01 Positive 90 (94.7) 8 (72.7) Any Prior Gene Testing No 55 (57.9) 2 (18.2) 0.01 Yes 40 (42.1) 9 (81.8) Other factors examined: Age at diagnosis, Histology, Stage, Bilaterality, Prior cancer (excluding non-melanoma skin), Family history configurations

9 Summary Table Mutated Gene Age at Dx PR status Histology, Stage Family Hx 1 st /2 nd * Ashkenazi Jewish + Prior Wilms Tumor Mutation not previously identified degree BR/OV Ca Clinical testing: BRCA, Panel BRCA1* 28 Positive Ductal, I Yes B1/2 founders BRCA1* 38 Negative Ductal, I Yes B1/2 founders BRCA1 41 Positive Ductal, I Yes BRCA full seq BRCA1 46 Negative Ductal, IIB Yes BRCA full seq BRCA2* 37 Positive Ductal, II Yes B1/2 founders BRCA2 42 Positive Ductal/Lob, IIB No Not done BRCA2, ATM 39 Positive Ductal/Lob, IIB No B2 single site, ATM ATM 47 Positive Ductal, II No BRCA + Panel CHEK Positive Ductal, I Yes BRCA full seq PALB2 25 Positive Ductal, IIA No BRCA + Panel PALB2 43 Negative Ductal, II No Not done

10 Conclusions Among women diagnosed age <50 with grade III ERpositive HER2-negative invasive breast cancer, the rate of BRCA1/2 mutation was 6.6%, and of any breast cancerassociated mutation with expanded NGS testing was 10.4%. Neither age at diagnosis nor family history distinguished carriers in this relatively small cohort of women diagnosed age <50.

11 Conclusions - 2 NCCN guidelines call for testing women with breast cancer diagnosed age 45, regardless of subtype. The mutation rate in high grade ER+HER2- tumors justifies testing in them. Panel testing identified mutations beyond BRCA1 and BRCA2 in women with high grade ER+HER2- tumors diagnosed age <50. Further research to assess the mutation rate in women diagnosed age >50 with grade III ER+ HER2- breast cancers is warranted.