prevalence of homologous recombination deficiency (hrd ... · prevalence of homologous...

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%


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


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%


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

BRCA1/2 Response to Platinum Chemotherapy

HR Deficiency, clinical impact • Germline BRCA1/2 mutation carriers respond favorably to PARP inhibitor

therapy


Tutt A, et al. Lancet, July 2010 Kaufman B, et al. J Clin Oncol. Jan 2015

Breast BRCA1/2 Response to Olaparib

ORR 41%

Advanced Cancer with gBRCA1/2 Response to Olaparib

Ovarian (N=193)

Pancreas (N=23)

Prostate (N=8)

Other* (N=12)

Response Rate

60 (31%) 5 (22%) 4 (50%) 1 (8%)

*biliary, bladder, colorectal, lung, esophageal, uterine

HR Deficiency, clinical impact • Advanced prostate cancer with

germline or somatic HRD: 88% response rate with olaparib

• Prolonged PFS with maintenance niraparib in recurrent ovarian cancer

– gBRCA: 21mo vs 5.5mo – HRD: 12.9mo vs 3.8mo

• Long-term response to maintenance olaparib in HRD ovarian cancer


Mateo J, et al. N Engl J Med, Oct 2015 Mirza MR, et al. NEJM, Dec 2016

Lheureux S, et al. Clin Cancer Res, Feb 2017

Prostate HRD Response to Olaparib

16/49 responders

(33%)

14/16 responders

(88%)

Methods AIM: Determine prevalence of HRD among all tumor lineages

• 53,619 solid tumors evaluated • Patient population: advanced malignancy, typically

refractory to chemotherapy • HRD defined: pathogenic or presumed pathogenic

somatic mutation of ATM, ATRX, BARD1, BLM, BRCA1/2, BRIP1, FANCA/C/D2/E/F/G/L, MRE11A, NBN, PALB2, PTEN, RAD50, RAD51, RAD51B, or WRN


Lineage N Ovarian 8,868

NSCLC 7,423

CRC 6,267

Breast 5,785

Endometrial 5,189

Pancreas 2,019

Melanoma 1,792

Sarcoma 1,760

Glioma 1,672

Unknown Primary 1,466

Neuroendocrine 1,440

Gastroesophageal 1,426

Cholangiocarcinoma/HCC 830

Cervix 791

Prostate 690

Head/Neck 642

Bladder 233

Kidney 219

GIST 201

Thyroid 191


• Multiplatform profiling at Caris Life Sciences DNA Sequencing (NGS or Sanger) for somatic mutations:

Illumina MiSeq platform (Illumina TruSeq Amplicon Cancer Hotspot panel, 47 gene)

NextSeq (Agilent SureSelect XT, 592 gene selected based on COSMIC database)

Pathogenic or presumed pathogenic ONLY considered

Methods

Results, Total HRD mutation frequency by lineage 14.1

9.7

8.0 7.4 7.1

6.5 6.4 6.3 5.2 5.1 4.8 4.8 4.3 4.0

2.8 2.6 2.2 1.9 1.4 1.3

0

5

10

15

HR

D M

utat

ion

Freq

uenc

y (%

)

Lineage


Results, HRD mutation landscape by lineage

0%

20%

40%

60%

80%

100%

Ovarian Bladder Breast Endometrial Prostate Pancreas

BRCA1

BRCA2

PTEN

ATM

PALB2

BRIP1

Prop

ortio

n of

Tot

al H

RD

Mut

atio

ns (%

)


N=8,868 14.1%

N=233 9.7%

N=5,785 8.0%

N=690 7.1%

N=5,189 7.4%

N=2,019 6.5%

8.2%

5.2%

3.1%

2.7%

2.6%

1.3%

2.7%

2.9%

3.1%

4.3%

28.1%

4.3%

2.2%

5.6%

1.1%

1.7%

2.8%

0

500

1000

1500

2000

2500

3000

3500

PTEN BRCA2 BRCA1 ATM PALB2

Bladder

Breast

Cervix

CRC

Endometrial

Gastroesophageal

Glioma

Head and Neck

Hepatobiliary

Kidney

Melanoma

NSCLC

Ovarian

Pancreas

Prostate

Sarcoma

SCLC

Thyroid

Unknown 1°

Results, HRD mutation frequency overall

BRCA1: 2.6% 860/33,508

BRCA2: 2.8% 949/34,127

PALB2: 0.5% 69/14,013

PTEN: 5.8% 3,107/53,619

Tota

l # H

RD

Mut

atio

ns

ATM: 1.2% 624/53,045


Overall Mutation Frequency: 13.0%

Results, Lineage impact by HRD mutation

0%

20%

40%

60%

80%

100%

PTEN BRCA2 BRCA1 ATM PALB2

Bladder

Breast

Cervix

CRC

Endometrial

Gastroesophageal

Glioma

Head and Neck

Hepatobiliary

Kidney

Melanoma

NSCLC

Ovarian

Pancreas

Prostate

Sarcoma

SCLC

Thyroid

Unknown 1°

Prop

ortio

n of

Tot

al H

RD

Mut

atio

ns (%

)



Results, Summary of HRD mutations identified Mutation %

PTEN 5.8 BRCA2 2.8 BRCA1 2.6

ATM 1.2 PALB2 0.5 NBN 0.1 BLM 0.1

BRIP1 0.01 No mutations identified

ATRX, BARD1, FANCA/C/D2/E/F/G/L, MRE11A, RAD50, RAD51, RAD51B, WRN

Results, Published HRD frequency comparisons PUBLICATION TUMOR TYPE MUTATIONS EVALUATED FREQUENCY

Witkiewicz AK, et al. (Nat Commun 2015)

Pancreas DNA repair genes including FA genes, ATM, CHEK2, BRCA1/2 >35.0% N=109

Yap KL, et al. (Clin Cancer Res 2014)

Bladder ATM, FANCD2, PALB2, BRCA1/2 34.4% N=81

Mateo J, et al. (NEJM 2015)

Prostate BRCA1/2, ATM, FANCA, CHEK2, PALB2, HDAC2, RAD51, MLH3, ERCC3, MRE11, NBN

33.0% N=43

Konstantinopoulos PA, et al. (Cancer Discov 2015)

Ovarian BRCA1/2, CDK12, RAD51C, FA genes, RAD50, PTEN, ATM, ATR, CHEK1, CHEK2

23.5% N=316

Stjepanovic N, et al. (SABS 2016)

Breast (TNBC) BRCA1/2, FA genes, BML, BARD1, BRIP1, CHEK2, FAM175A, NBN, PALB2, PTEN, RAD51D, TP53

15.6% N=32

Shahda S, et al. (GI ASCO 2017)

Pancreas BRCA1/2, ATM, ATR, BRIP1, FA genes 15.4% N=78

Bang YJ, et al. (JCO 2015)

Gastric ATM (expression) 14.0% N=123

Heeke AL, et al. (ASCO 2017)

All tumor types ATM, ATRX, BARD1, BLM, BRCA1/2, BRIP1, FANCA/C/D2/E/F/G/L, MRE11A, NBN, PALB2, PTEN, RAD50, RAD51, RAD51B, WRN

13.0% N=53,619

Pennington KP, et al. (Clin Cancer Res 2014)

Ovarian BRCA1/2, ATM, BARD1, BRIP1, CHEK1, CHEK2, FAM175A, MRE11A, NBN, PALB2, RAD51C, RAD51D

9.0% N=357

Matsuda N, et al. (Breast Cancer Res Treat 2017)

Breast PTEN, ATM, CDKN2A, NPM1 1.9% N=400


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


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


Limitations • Unknown if somatic mutations represent germline mutations

• Overrepresentation of ovarian tumors

• Pathogenicity defined as of 2017

• Mutational load, and its significance, not assessed


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


Acknowledgments • Georgetown Lombardi Comprehensive Cancer Center

– Claudine Isaacs, MD – Michael Pishvaian, MD, PhD – Filipa Lynce, MD – John Marshall, MD

• Caris Life Sciences

– Tabari Baker, PhD – Wangjuh (Sting) Chen, PhD

• The Conquer Cancer Foundation


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