1. AACR Think Tank on Genomics in Clinical Medicine
Germline Testing: Therapeutic implications and other interesting challenges
AACR Think Tank on Genomics in Clinical Medicine
Judy E. Garber, MD MPH Dana-Farber Cancer Institute Boston, MA July 2016

2. Examples of Surgical Implications
Lynch Syndrome: total colectomy v. partial colectomy
BRCA: bilateral mastectomy v. breast conservation
Cowdens: TAH/BSO vs. RRSO, Total thyroidectomy v. partial thyroidectomy
VHL: Renal tumor targeted resections vs. partial or unilateral nephrectomy

3. Response to Neoadjuvant Cisplatin in BRCA1+ Breast Cancer Patients
107 women with BRCA1 germline mutations
4 cycles CDDP 75mg/m2 q 21d
Feature
Number
Path CR Rate
Age 20-40
28 / 43 65
Age 61-80
2 / 7 29
<2cm
40 / 55 73
>2cm
25 / 52 48
Estrogen Receptor -
52 / 86 61
ER +
9 / 16 56
Lymph nodes +
15 / 38 39
Lymph nodes -
50 / 69 71
Prior Chemo
6 / 14 43
PathCR Rate
65/107 = 61%
Byrski T et al. Br Ca Res Treat 2014

4. Absolute difference (C-D)
TNT Trial: Objective response by BRCA1/2 status
Germline BRCA1/2
Mutation (n=43)
Absolute difference (C-D)
34.7% (95% CI 6.3 to 63.1)
Exact p = 0.03
NO Germline BRCA1/2
Mutation (n=273)
Absolute difference (C-D)
-8.5% (95% CI to 2.6)
Exact p = 0.16
36/128
(28.1%)
53/145
(36.6%)
Interaction: randomised treatment & BRCA 1/2 status: p = 0.01

5. Genomic Aberrations in DNA Repair in 48 Patients with Metastatic, Castration-Resistant Prostate Cancer Predict Response to Olaparib, a PARP inhibitor
Responders: Germline 3 BRCA2, 2 ATM
Somatic: diverse
Mateo J et al. N Engl J Med 2015; 373:

6. Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 Mutation
Kaufman B et al. J Clin Oncol 2015;33:

7. Single Agent Olaparib in Metastatic Breast and Ovarian Cancer +/- BRCA
TNBC: No responses if BRCA1/2 –
Ovarian: Responses in BRCA1/2+ and WT
Gelmon KA et al. Lancet Oncol 2011;12:852-61

8. Swisher E et al. Ca Res 2008;68:2581-2586
Ovarian Cancers from women with a germline BRCA1/2 mutation acquire resistance to Carboplatin by reverting their mutation
BRCA1 mutation 187delAG
BRCA2 mutation 6174delT
Germline
Tumor
Swisher E et al. Ca Res 2008;68:
Sakai W et al. Nature 2008;451:

9. Telomeric Allelic Imbalance Score and Cisplatin Response in two Breast Cancer Trials
Birkbak NJ et al. Cancer Discovery, 2012

10. Bertagnolli M et al. JCO 2009;27:1814-1821
(A) Overall survival and (B) disease-free survival for 702 Colon cancers by MMR status by treatment groups
(A) Overall survival for mismatch repair (MMR) status by treatment groups (n = 702); (B) disease-free survival for MMR status by treatment groups (n = 702). FU, fluorouracil; LV, leucovorin; MSI LS, microsatellite instability low/stable; MSI H, microsatellite instability high; IFL, irinotecan, fluorouracil, and leucovorin; NA, not applicable.
Bertagnolli M et al. JCO 2009;27:

11. Relationships between genes and signalling pathways involved in inherited colorectal cancer syndromes
Diagram illustrating relationships between genes and signalling pathways involved in inherited colorectal cancer syndromes. FAP, familial adenomatous polyposis syndrome; HMPS, hereditary mixed polyposis syndrome; JPS, juvenile polyposis syndrome; LS, Lynch syndrome; MAP, MUTYH-associated polyposis; NTHL1, NTHL1-associated polyposis; PJS, Peutz–Jeghers syndrome; PPAP, polymerase proofreading-associated polyposis syndrome.
Short E et al. J Med Genet 2015;52:

12. Therapeutic Approaches for Lynch Syndrome Carriers Combining Immune checkpoint Inhibitors and DC Vaccination
Westdorp R et al. Ca Immunol Immunother epub Apri 2016

13. Radiographic objective responses to Vandetanib in adolescents and children with MEN2 and Medullary Thyroid Cancer
Radiographic objective responses in adolescents and children with MEN2B and MTC. A, CT of chest and neck in patient 1 (15-year-old female). B, CT of chest in patient 4 (11-year-old male). CT, computer tomography.
Fox E et al. Clin Cancer Res 2013;19:

14. AZD9291, a T790M-directed EGFR TKI in patients with germline EGFR T790M
2 patients with advanced NSCLC and germline T790M have received AZD9291, a T790M-directed EGFR TKI2
No unexpected toxicities were seen, suggested no inhibition of the germline T790M allele
One 62 year-old female with brain mets has had a partial response lasting >11 months
Jänne P et al, NEJM, 2015

15. Is Li Fraumeni defined by clinical features or germline TP53 mutation?

16. Test Result Single Gene Test (n=2,956) All Multi-gene Panels
Single gene (SG) vs. Multi-gene panel (MGP) testing for TP53 germline mutations in Li Fraumeni syndrome (LFS)
Rana HQ et al. ASHG 2015
Test Result
Single Gene Test
(n=2,956)
All Multi-gene Panels
(n=22,226) n %
TP53+
118
4.0* 69
0.31*
TP53 VUS 39
1.3
101
0.45
TP53-
2,802
94.7
22,055
99.2

17. Low allelic fraction TP53 mutations in a large germline panel cohort
46/128 (35.9%) individuals with a TP53 PV displayed allelic imbalance (allelic fraction <20%), suggesting somatic mosaicism.
Demographics and Clinical Characteristics of Individuals with a PV in TP53
Variables
Likely Germline
(n=82)
Likely Somatic (n=46)
Remaining Testing Cohort
(n=135,481)
Age at Testing N 82 45
135332
Mean (SD)
45.9 (16.14)
59.2 (14.90)
48.6 (13.52)
Age at First Cancer Diagnosis 72 44
62202
40.0 (15.25)
49.3 (13.91)
49.1 (12.74)
Cancer Status
Affected
73 (89.0%)
44 (95.7%)
63638 (47.0%)
Diagnosed with Breast Cancer
55 (67.1%) 28
43,472 (32.1%)
Diagnosed ≤35
24 (43.6%)
6 (21.4%)
3,632 (8.4%)
Met Testing Guidelines
31 (37.8%)
5 (11.1%) --
Somatic v Germline TP53 PV: ▪ Older mean age at dx ▪ Higher proportion of affected individuals ▪ Lower incidence of Br Ca < age 35 in women
Myriad SABCS 2015

18. Clonal Hematopoiesis and Blood Cancer Risk
“About 10% of people older than 70 years of age carry one or more mutations in their hematopoietic cells, and these persons have a higher relative risk of a hematologic cancer (by a factor of 11) and of death from cardiovascular disease (by a factor of 2.0 to 2.6).”
Jaiswal S et al. N Engl J Med 2014;371:

19. Commercial venture: Screening circulating DNA for early cancer detection

20. Whole Genome View of Copy Number Changes in Cases of Maternal Cancer
Bianchi D et al. JAMA 2015;314:162-9

21. +
Many people still get tested in order to provide information to other family members, especially their children.

22. Nolan E et al. Nature Med epub 20 Jun 2016

23. RankL inhibition markedly attenuates tumor onset in BRCA1 deficient mice
Nolan E et al. Nature Med epub 20 Jun 2016