in Breast Cancer

(1)

Precision Medicine in Breast Cancer

Lee Kyoung Eun

Hematology-Oncology

Ewha Womans University Hospital

2017년 대한내과학회 혈액종양내과분과 춘계 연수강좌

(2)

Biomarker?

Observation

• Many genomic aberrations are across multiple cancers

Question

• Is presence of genomic

aberration more predictive of drug sensitivity than

histology of tumor?

(3)

Personalized medicine?

“a form of medicine that uses information about a person’s genes, proteins and environment

to prevent, diagnose and treat disease” by NCI

(4)

Personalized medicine?

“a form of medicine that uses information about a person’s genes, proteins and environment

to prevent, diagnose and treat disease”

(5)

Molecular Aberrations Defining Administration of Approved Targeted Agents in Different Solid Tumor Diagnoses

ASCO Education Book 2015

(6)

Today’s Talk EBC

• Is adjuvant chemotherapy fit for all patients?

• TAILORx, MINDACT

• New agent and pCR?

• I-SPY 2

ABC

• Targeting drug

• PIK3CA : FERGI, BELLE2, SAFIR01

• Drug resistance

• ESR1 : BOLERO2 sub-analysis

• DNA repair

• BRCA1/2 : prECOG0105

• Innovative clinical trial designs

(7)

Approaches of Next-Generation Sequencing

ASCO Education Book 2015

(8)

Molecular Profiling

Clarifying subtypes

Proc Natl Acad Sci U S A. 2001 Sep 11;98(19):10869-74. Annual Report on Cancer in the US:1975-2011

(9)

Molecular classification based on IHC : Daily Practice

Carey, L. A. et al. JAMA 2006;295:2492-2502; Lehmann BD et al. J Clin Invest 2011 121:2750

high Ki67/- low Ki67

(10)

Early Breast Cancer

(11)

Not all BC with similar clinical features have the same biologic behavior

• Possibility of

“overtreating” subsets who have truly localized disease CURED by

surgery

• Possibility of

“undertreating” subsets whose cancer is NOT

SENSITIVE to the delivered drug

Walgren et al. J Clin Oncol 23:7342-7349

(12)

Biomarkers in EBC?

• For women with early-stage breast cancer, with known ER, PR, HER2 status, are there additional biomarkers?

• Q: Who can be spared therapy? A: Prognostic markers needed

• Q: Which therapy will work best ? A: Predictive markers needed

Gyorffy et a. Breast Cancer Research (2015) 17:11

(13)

Multigene assays

Critical Reviews in Oncology/Hematology 91 (2014) 223–233

(14)

21-gene recurrence score

Oncotype DX

^TM

• HR(+), HER2(-), Node(-) breast cancer

• RT-PCR assay, 21 genes, paraffin-embedded tissue

• In NSABP B-14

• Predict the risk of distant relapse after 18 years for patients with Node(-) BC

• In NSABP B-20

• RS correlates with benefit from chemotherapy in ER(+) tumors

• In TransATAC

• For Node(+) & (-) group, independent predictor of distance recurrence

• Ongoing prospective trial

• Hormone Therapy With or Without Combination Chemotherapy in Treating Women Who Have Undergone Surgery for Node-Negative Breast Cancer (The TAILORx Trial)

Paik et al. N Engl J Med 2004;351:2817-26

(15)

Validated as quantifying the likelihood of distant recurrence in tamoxifen-treated, Node(-), ER(+) breast cancer

Category RS 10y risk (%)

Low RS<18 6.8

Intermediate 18≤ RS <31 14.3

High RS ≥ 31 30.5

21-gene recurrence score

Oncotype DX

^TM

Paik et al. N Engl J Med 2004;351:2817-26

(16)

Largest Benefits of Tamoxifen Observed in

Low and Intermediate Risk Groups (NSABP B-14)

(17)

Largest Benefits of Chemotherapy Observed

in High Risk Groups (NSABP B-20)

(18)

(19)

Trial Assigning IndividuaLized Options for Treatment

The TAILORx : 21-gene prospective trial

OncotypeDX

RS ≤ 10

Hormone Rx

RS > 25

Chemotherapy + Hormone Rx RS 11-25 : Randomize

Hormone Rx vs.

Chemotherapy + Hormone Rx

Node-negative, ER-positive Breast Cancer

15.9% 67.3% 16.9%

2006-2010 N=10,253

(20)

OncotypeDX

RS ≤ 10

Hormone Rx

RS > 25

Chemotherapy + Hormone Rx RS 11-25 : Randomize

Hormone Rx vs.

Chemotherapy + Hormone Rx

Node-negative, ER-positive Breast Cancer

Trial Assigning IndividuaLized Options for Treatment

(21)

OncotypeDX

RS ≤ 10

Hormone Rx

RS > 25

Hormone Rx vs.

Trial Assigning IndividuaLized Options for Treatment

(22)

OncotypeDX

RS ≤ 10

Hormone Rx

RS > 25

Hormone Rx vs.

Invasive DFS 99.3%

Freedom from

recurrence at 5y 98.7%

OS 98.0%

Sparano et al. N Engl J Med 2015;373:2005-14

Trial Assigning IndividuaLized Options for Treatment

(23)

Dowsett et al. J Clin Oncol 28:1829-1834

21-gene recurrence score

“How about in node-positive patients?”

• For prediction of risk

• Post-menopausal

• TransATAC

In Node + patients, withholding the chemotherapy is NOT recommended now

RxPONDER trial Node negative

Node positive

(24)

70-gene signature Mammaprint

^®

• FDA-approved for prognostication of patients with stage I, II node(-) BC with tumors <5cm

• Requires fresh or frozen samples (tumor cell content > 30%)

• Strong prognostic power

• Predicts the benefits of adding

chemotherapy to endocrine therapy in the poor prognosis group, N=541

Knauer M et al. Breast Cancer Res Treat (2010) 120:655–661

Low risk group High risk group

(25)

MINDACT trial

• Prospective,

Randomized, phase III, EBC

• From 2007 to 2011, N=6,693

• Clinical risk vs.

Genomic risk (Adjuant!

Online & MammaPrint)

N Engl J Med 2016;375:717-29

(26)

94.4%

95.9%

MINDACT trial

95.8%

95.0%

High clinical risk : 3356 pts

High clinical risk /low genomic risk : 1550 pts

So, 46.% of high clinical risk might not require chemotherapy

N Engl J Med 2016;375:717-29

(27)

I-SPY 2

Investigation of Serial Studies to Predict Your Therapeutic Response through Imaging and Molecular Analysis 2

• Multicenter, adaptive phase 2 trial for high-risk clinical stage II or III BC

• Neoadjuvant therapy

• Adjuvant

: large sample, many years, small improvements in outcome

• So, neoadjuvant!

• New approach to trial design

• Rather than fixed framework of statistical assumption(size, power)

• So, adaptive approach

• Basis of the Bayesian probability assumptions

• “graduated” to the next phase of investigation

• Faster and more flexible trial design

(28)

I-SPY 2

N Engl J Med 375;1

Clin Pharmacol Ther. 2009 Jul;86(1):97-100

HR HER2 MammaPrint score

Patient Stratification

(29)

Adaptive Randomization of Neratinib in EBC exclude HR+& low risk score

N Engl J Med 2016;375:11-22

(30)

N Engl J Med 2016;375:11-22

(31)

N Engl J Med 2016;375:11-22

(32)

Adaptive Randomization of

Veliparib–Carboplatin Treatment in BC

N Engl J Med 2016;375:23-34

(33)

N Engl J Med 2016;375:23-34

(34)

Advanced Breast Cancer

Targeting drug, overcoming the resistance

(35)

Potential applications of genomics for MBC

Application Technology Targets LoE

Drivers(DNA) NGS, if multiple genes validated ERBB2 amplification I PIK3CA mutation II AKT1 mutations III ERBB2 mutations III Drivers(RNA/proteins) Gene expression, phosphoprotein assays ER expression I

mTOR activation ND CDK4/6 activation ND Lethal subclone Ultra-deep sequencing, ctDNA ESR1 mutations III DNA repair Targeted sequencing, WES, SNP arrays BRCA1/2 mutations I/II

Immune system WES, RNA sequencing PD-L1 overexpression ND

Neoantigen

(36)

Oncogenic drivers

• Historic 2 drivers

• ER expression and ERBB2 amplification

• PIK3CA mutation

• 25% of BC

• Mainly with ER or HER2 expression

• mTOR inhibitor, AKT inhibitor, nonselective PI3K inhibitor, α-selective PI3K inhibitor

• But in BOLERO-2, no predictive for the efficacy

• FGFR1 amplification

• 10% of BC, mainly with ER expression

• Failed in phase 1 trial

• CCND1 amplification

• 15% of BC, failed

• ERBB2 mutation (activating mutation)

• Ongoing phase II with neratinib

(37)

Oncogenic drivers

• Historic 2 drivers

• ER expression and ERBB2 amplification

• PIK3CA mutation

• 25% of BC

• Mainly with ER or HER2 expression

• mTOR inhibitor, AKT inhibitor, nonselective PI3K inhibitor, α-selective PI3K inhibitor

• But in BOLERO-2, no predictive for the efficacy

• FGFR1 amplification

• 10% of BC, mainly with ER expression

• Failed in phase 1 trial

• CCND1 amplification

• 15% of BC, failed

• ERBB2 mutation (activating mutation)

• Ongoing phase II with neratinib

(38)

Arm N PFS(m)

FERGI Ful 231 5.1

Ph2 (2016) Ful+Pictilisib 243 6.6 HR 0.7 (95%CI, 0.52-1.06; p=0.096)

BELLE-2 Ful 571 5 Prior AI,

Ph3 (2016) Ful+Buparlisib 576 6.9 HR 0.78 (95%CI, 0.67-0.89;p<0.001)

PI3K inhibitors

• Pan class I inhibitors

• Buparlisib & pictilisib

• Alpha-specific inhibitors

• Alpelisib & taselisib

Krop I et al. Cancer Res 2015;75:S2-02, Baselga J et al. Cancer Res 2015;76 (4 suppl; abstr S6-01)

(39)

PI3K inhibitors : FERGI trial

• Pictilisib : oral inhibitor of multiple PI3K isoforms

• Two-part, randomised, double-blind, placebo-controlled, phase 2 study

• Post-menopausal, HR+/HER2-, endocrine resistant

• with PIK3CA mutation

• Fulvestrant +/- pictilisib (daily 340mg in part 1, 260mg in part 2)

Lancet Oncol 2016; 17: 811–21

(40)

PIK3CA mutation status does not predict benefit of the addition of pictilisib to fulvestrant

Intention-to-treat population PIK3CA-Mutant Population

PFS Based on Tumor PIK3CA Mutation Status

PI3K inhibitors : FERGI trial

Lancet Oncol 2016; 17: 811–21

(41)

PI3K inhibitors : BELLE-2 trial

CI, confidence interval; ctDNA, circulating tumor DNA; HR, hazard ratio; PFS, progression-free survival.

ctDNA PIK3CA Mutant n=200

Buparlisib + Fulvestrant

n=87

Placebo + Fulvestrant

n=113 Median PFS, months

(95% CI)

7.0 (5.0–10.0)

3.2 (2.0–5.1)

HR (95% CI) 0.56 (0.39–0.80)

One-sided nominal P val

ue <0.001

ctDNA PIK3CA Non-mutant n=387

Buparlisib + Fulvestrant

n=199

Placebo + Fulvestrant

n=188 Median PFS, months

(95% CI)

6.8 (4.7–8.5)

6.8 (4.7–8.6)

HR (95% CI) 1.05 (0.82–1.34)

One-sided nominal P value 0.642

Probability of Progression-free Survival, %

Time (Months) 100

60

0 80

40

20

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 Buparlisib + fulvestrant (n/N

=124/199)

Placebo + fulvestrant (n/N=

126/188)

Probability of Progression-free Survival, %

Time (Months) 100

60

0 80

40

20

0 2 4 6 8 10 12 14 16 18 20 22 Buparlisib + fulvestrant (n/N=4 8/87)

Placebo + fulvestrant (n/N=90/

113)

Baselga J et al. S6-01 2016 SABCS

(42)

SAFIR01/UNICANCER

• Multicenter molecular screening, 2011.6-2012.7

• Metastatic breast cancer with accessible biopsy, France

• Comparative genomic hybridization(CGH) array and Sanger sequencing on

PIK3CA

(exon 10 and 21),

AKT1

(exon 4)

• Primary object

• 30% of patients in clinical trial setting with targeted agents

• 423 pts, CGH array(67%), Sanger sequencing(70%)

• 43 pts (9%) : received targeted therapy

Lancet Oncol 2014; 15: 267–74Lancet Oncol 2014; 15: 267–74

(43)

Distribution of targetable genomic alterations among screened patients

25%

19%

13%

Rare(<5%), 39%

(44)

Genomic alteration and matched targeted therapies

• N= 43 pts

• 9% of objective response

• 21% of stable disease

• For more than 16 weeks

• SE related to biopsy (4 pts)

• Pneumothorax (1 pt)

• Pain (1 pt)

• Hematoma (1 pt)

• Hemorrhagic shock (1 pt)

(45)

Activating HER2 mutations

in HER2 gene amplification(-) BC

 HER2 mutation (7/13 activating mutation)

 G309A, D769H, D769Y, V777L, P780ins, V842I, and R896C

 Sensitive to the irreversible kinase inhibitor, neratinib

 Ongoing phase2 neratinib in MBC

Cancer Discov. 2013 Feb 3(2): 224–237

(46)

Drug resistance – ESR1 mutation

• ESR1 : Encodes ER

• Less than 1% of EBC, but increasing to 10~30% of AI resistance tumors

• Hotspot mutation leading to ligand-independent activation of receptor

• Benefit from high dose fulvestrant?

(47)

BOLERO-2

: Everolimus in Postmenopausal Hormone- Receptor–Positive Advanced Breast Cancer

Stratification : sensitivity to prior hormone therapy and presence of visceral metastasis Primary end point :PFS, secondary end point :OS, ORR, QOL, safety, bone marker, PK

Phase III N=724

-Postmenopausal, ER+

-Unresectable locally advanced or metastatic

-Recurrence or progression after letrozole or

anastrozole ^{R 2:1}

Baselga et al. N Engl J Med 2012;366:520-9

N=485

EVE 10mg daily +EXE 25mg daily

N=239

Placebo+EXE 25mg daily

(48)

Baselga et al. N Engl J Med 2012;366:520-9 Yardley et al. Adv Ther 2013 Oct;30(10):870-84.

BOLERO-2 : PFS (Final 18-month follow up)

(49)

A Secondary Analysis of the BOLERO-2 Clinical Trial

• Prevalence of

ESR1

Mutations in cfDNA and Outcomes in MBC

• 2014.12-2015.8

• 74.7% cfDNA from baseline plasma samples of pts (available 541/724 pts)

• Objects : effect of ESR1 mutation on OS, PFS by treatment arm

• Methods : droplet digital PCR

JAMA Oncol. 2016;2(10):1310-1315.

(50)

A Secondary Analysis of the BOLERO-2

ESR1 Mutation Frequency

JAMA Oncol. 2016;2(10):1310-1315.

(51)

A Secondary Analysis of the BOLERO-2

OS according to ESR1 Mutation

32.1 m [95%CI, 28.1-36.4]

25.9 m [95%CI, 19.2-32.4]

19.9 m [95%CI, 13.0-29.3]

15.1 m [95%CI, 10.8-27.4]

JAMA Oncol. 2016;2(10):1310-1315.

(52)

A Secondary Analysis of the BOLERO-2

PFS by treatment & ESR1 Mutation

The D538G group (hazard ratio, 0.34 [95%CI, 0.02-0.57]) derived a similar PFS benefit as wild type from addition of everolimus to exemestane

JAMA Oncol. 2016;2(10):1310-1315

(53)

ESR1 mutations are rarely acquired during adjuvant AI, and frequently during metastatic AI therapy

• Multiplexed digital PCR assays for ESR1 mutations in ctDNA

• ESR1 mutations : shorter PFS on subsequent AI-based therapy (HR 3.1, 95%CI 1.9-23.1, p=0.0041)

• ESR1 mutation prevalence differed markedly between patients that were first exposed to AI during the adjuvant and metastatic settings (5.8% (3/52) vs 36.4% (16/44) respectively, p=0.0002).

Sci Transl Med. 2015 November 11; 7(313): 313ra182

(54)

Angelina Jolie Effect

• On Feb 16, 2013 Jolie underwent double mastectomy

• Family tree warranted genetic testing for

BRCA mutation

• Found out 87% of risk in developing cancer

• Mastectomy lowered this risk to under 5%

(55)

 Combination of mutations in 2 or more genes leads to cell death

 Mutation in a single gene does not Gene A Gene B Cell survival

– –

+ +

+ –

– +

Synthetic Lethality

(56)

Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and advanced breast cancer

: a proof-of-concept trial

Tutt et al, Lancet 376(9737)July 2010, 235-244

• Confirmed BRCA1 or BRCA2 mutation

• Advanced refractory breast cancer

(stage IIIB, C/IV) after failure of ≥1 prior chemotherapy

Olaparib 400mg BID, 28-days cycle (N=27) Cohort 1 (enrolled first)

Olaparib 100mg BID, 28-days cycle (N=27)

Cohort 2

Multicenter, phase II, single arm, sequential trial First report of clinical trial targeting BRCA1/2 BC

(57)

(58)

G3/4 AE, n(%) Olaparib 400mg BID

(n=27)

Olaparib 100mg BID

(n=27)

Fatigue 4 (15) 2 (7)

Nausea 5 (19) 0

Vomiting 3 (11) 0

Headache 0 1 (4)

Best % Change from Baseline

400mg

bid 100mg

bid

Olaparib was well tolerated in BRCA1/2 carriers with a similar side effect profile to experience in non-carriers.

(59)

PrECOG 0105

• Phase II Study, neoadjuvant

• Gemcitabine, Carboplatin, Iniparib(5.6 mg/kg IV on days 1, 4, 8, and 11)

• In triple-Negative or BRCA1/2 Mutation

• Tumor-Based Measure of Genomic Instability

• pCR 36%

J Clin Oncol 33:1895-1901

(60)

Genotype-Driven Clinical Trials Principles

• Patients will be matched to the trials according to the

molecular profiling of the their disease as defined by the results of the tumor gene sequencing or other molecular technique

• Molecular aberrations in tumor are dictating sensitivity to targeted therapies

(61)

Examples of clinical trials designs

: based on molecular biomarker assessment

Hayes DF, et al., Trans Am ClinClimatolAssoc, 2015

(62)

Clinical Trials of Precision Medicine

• Longitudinal cohort studies with or without downstream trials

• Studies assessing the clinical utility of molecular profiling

• Master or umbrella trials

• Basket trials

• N-of-1 trials

• Adaptive design trials

• Window-of-Opportunity trial

(63)

Clinical Trials of Precision Medicine

• Basket trials

• N-of-1 trials

(64)

The AURORA initiative for MBC

• Multinational, collaborative metastatic breast cancer molecular profiling programme by Breast International Group(BIG)

• Tissue from at least one metastatic lesion, either collected

prospectively or from archived samples up to 6 months old (FFPE and frozen tissue)

• Archived FFPE tissue from the primary tumor

• Whole blood samples

• Plasma samples

• Serum samples

British Journal of Cancer (2014) 111, 1881–1887

(65)

(66)

Clinical Trials of Precision Medicine

• Basket trials

• N-of-1 trials

(67)

Umbrella Trial Basket Trial

JAMA Oncol. 2017;3(3):423

Umbrella Trial Basket Trial

(68)

Umbrella or Basket trials

• I SPY : Investigation of Serial Studies to Predict Your Therapeutic Response With Imaging And moLecular Analysis trials in breast cancer

• Ph2, randomized adaptive “umbrella trial” in high-risk neoadjuvant BC

• Lung MAP : Lung Master Protocol trial in advanced squamous lung cancer

• ALCHEMIST : Adjuvant Lung Cancer Enrichment Marker Identification and Sequencing Trial in surgically resected NSCLC

• LCMC : Lung Cancer Mutation Consortium -associated trials in advanced lung adenocarcinoma

• BATTLE : Biomarker-integrated Approaches of Targeted Therapy for Lung Cancer Elimination program

• Prospective, biopsy-mandated, biomarker-based, adaptive randomized clinical trial platform for patients with advanced NSCLC

• NCI MATCH : NCI-Molecular Analysis for Therapy Choice Trial

• PhII Basket, Aug 2015, “actionable mutation”

• TAPUR : Targeted Agent and Profiling Utilization Registry

Ann Transl Med 2016;4(24):529

(69)

Clinical Trials of Precision Medicine

• Basket trials

• N-of-1 trials

(70)

• Based on modifying parameters (dose, sample size, drug,

schedule…) of a clinical trial evaluating a treatment in accord with observed outcomes in participants

Eisenstein M,etal., Nature, 2014; 509:S55-57, AwadaA, ESMO

(71)

Adaptive trial design

PROS

• Faster evaluation of the drug

• Modification of drug, dosage and sample size during the trial according to the

observed results

CONS

• Practical difficulties during the performance of the trial

• The clinicians are not familiar with the essential statistical part of this approach

• Active and dynamic follow- up of the trial is needed

(72)

Clinical Trials of Precision Medicine

• Basket trials

• N-of-1 trials

(73)

Window –of –Opportunity trials

• Assessing the administration of an investigational agent over a short period of time

• Most often in the pre-surgical setting

• No major efficacy endpoint

•

In vivo

biological effect (pharmacodynamics) of an experimental agent

(74)

D-BEYOND trial in EBC

ClinicalTrials.gov NCT01864798

(75)

Window –of –Opportunity trials

PROS

•

In vivo

evaluation of the mechanism of action of a drug or if the target is

affected

CONS

• No direct clinical implication

• Short period treatment

(76)

Examples of genotype-driven clinical trials in breast cancer

Trial Phase(N) compound Molecular mechanism of action of experimental drug

Type of disease Molecular aberration

NCT01219699 I (200) BYL719 PI3Ka Inhibitor Solid tumours and

ER+MBC PIK3CA mutations

NCT01589861

(PIKHER2) I/II (106) BKM120 Pan-PI3K Inhibitor HER2-amplified MBC PTEN loss and/or PIK3CA mutations

NCT01277757 II (40) MK2206 AKT Inhibitor MBC AKT mutations and/or

PIK3CA mutations and/or PTEN loss NCT01202591

(GLOW) I/II (900) AZD4547 FGFR Inhibitor ER+ MBC FGFR1 amplification

NCT02053636

(FINESSE) II (123) Lucitanib FGFR Inhibitor ER+ MBC FGFR1 amplification

NCT01670877 II (29) Neratinib Irreversible EGFR/HER2

inhibitor HER2-amplified MBC ERBB2 mutations

(77)

Take Home Messages

• Molecular subtypes with gene expression profiles in BC

• Avoidance of chemotherapy in subgroups of HR+/HER2- BC with multigene assay kit

• Possible biomarkers for inhibition of oncogenic drivers

(

PIK3CA, ERBB2

mutation), drug resistance (

ERS1

mutation) and DNA repair (

BRCA1/2

mutation)

• Application of innovative clinical trial design

(78)