Prevalence of Homologous Recombination Deficiency (HRD) Among All Tumor Types Arielle Heeke 1 , Filipa Lynce 1 , Tabari Baker 2 , Michael Pishvaian 1 , Claudine Isaacs 1 1 Lombardi Comprehensive Cancer Center, Georgetown University, Washington DC 2 Caris Life Sciences, Inc.
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Prevalence of Homologous Recombination Deficiency (HRD) Among
All Tumor Types
Arielle Heeke1, Filipa Lynce1, Tabari Baker2, Michael Pishvaian1, Claudine Isaacs1
1 Lombardi Comprehensive Cancer Center, Georgetown University, Washington DC
2 Caris Life Sciences, Inc.
Financial Disclosures • Nothing to disclose
Presented by: Arielle Heeke, MD
Homologous Recombination, BRCA1/2
• BRCA1/2 integral for genomic integrity • Mutation carriers with lifetime risk of developing breast cancer up to
80%
Presented by: Arielle Heeke, MD
MRNc
MRNc
RAD51
BRCA1
RAD51
BRCA2 BRCA2
BRCA2
BRCA1
RAD51
3’
3’
5’
5’
Mavaddat, et al. J Natl Cancer Inst, June 2013
Homologous Recombination, BRCA1/2
Presented by: Arielle Heeke, MD
MRNc
MRNc
MRN Complex: Rad50, MRE11, NBN
DNA DAMAGE
ATM ATM H2AX
CHK2 p53
Increased expression of genes involved in DNA repair
3’
5’ 3’ RAD51 RAD51 RAD51
BRCA2 BRCA2 BRCA2
5’ PALB2
BRCA1
BRCA1
BARD1
CHK2
BLM
BRIP1
WRN
PTEN
FANC
HR Deficiency, clinical impact
• Germline BRCA1/2 mutation carriers respond favorably to platinum-based chemotherapy
– MyChoice® HRD score high TNBC responds better to platinum neoadjuvant therapy (pCR 50% versus 7.7%)
– 84% of ovarian tumors with HRD platinum sensitive versus 60%
Presented by: Arielle Heeke, MD
STUDY POPULATION RESPONSE
Vencken et al. (Ann Oncol 2011)
BRCA1/2 and sporadic ovarian cancer (n=334)
NED/CR BRCA1/2 88% (platinum) vs sporadic 71% (platinum)
Tutt et al. (SABCS 2014)
Advanced TNBC or BRCA1/2 (n=376)
ORR BRCA1/2 mutated: 68% (carboplatin) vs 33% (docetaxel)
Golan et al. (Br J Cancer 2014)
BRCA1/2 pancreatic cancer (n=71)
OS 22 mo (platinum) vs 9 mo (non-platinum chemotherapy)
Pennington, et al. Clin Cancer Res, Feb 2014 Telli ML, et al. Clin Cancer Res, Aug 2016
ACTIVE TRIALS: – Maintenance rucaparib in advanced ovarian cancer stratified by HRD – Olaparib in ovarian cancer with HRD, stratified by testing type – Prexasertib in solid tumors with HRD – Nivolumab in prostate cancer with HRD – Intensified neoadjuvant chemotherapy in TNBC with HRD
COMBINATION THERAPIES – Paclitaxel/olaparib vs paclitaxel/carboplatin in neoadjuvant HER2 negative
breast cancer with HRD – Olaparib/trabectedin in solid tumors with HRD – Olaparib and XRT in H&N SCC and inoperable breast cancer with HRD
HR Deficiency, future directions
Presented by: Arielle Heeke, MD
Niraparib Plus Carboplatin in Patients with Homologous Recombination Deficient Advanced Solid Tumor Malignancies
• Pre-identified patients with germline or somatic mutation by NGS in one of following genes: ARID1A, ATM, ATRX, MRE11A, NBN, PTEN, RAD50/51/51B, BARD1, BLM, BRCA1, BRCA2, BRIP1, FANCA/C/D2/E/F/G/L, PALB2, WRN, CHEK2, CHEK1, CDKN1A/B/C, CDKN2A, BAP1, FAM175A, SLX4, MLL2 or XRCC
• Primary endpoint: RP2D and schedule of niraparib + carboplatin • Correlatives: assess measures of DNA damage and repair, PARPi resistance
• Anticipated enrollment initiation: July 2017
Presented by: Arielle Heeke, MD
Limitations • Unknown if somatic mutations represent germline mutations
• Overrepresentation of ovarian tumors
• Pathogenicity defined as of 2017
• Mutational load, and its significance, not assessed
Presented by: Arielle Heeke, MD
Conclusions • HR mutations present in 13.0% of tumors
• Most commonly mutated lineages include ovarian (14.1%), bladder (9.7%), breast (8.0%), endometrial (7.4%), prostate (7.1%), and pancreas (6.5%)
• Most commonly mutated HR genes include PTEN (5.8%), BRCA2 (2.8%), BRCA1 (2.6%), and ATM (1.2%)
– BRCA1/2 mutations significant among female malignancies and CRC – PALB2 mutations appreciated in 2.7% of bladder tumors; also seen in pancreatic
cancer, NSCLC, CRC
Presented by: Arielle Heeke, MD
Acknowledgments • Georgetown Lombardi Comprehensive Cancer Center
– Claudine Isaacs, MD – Michael Pishvaian, MD, PhD – Filipa Lynce, MD – John Marshall, MD