Transforming treatment and improving survival for ovarian cancer patients

Laura Shawver, PhDFounder

Applications of genomic profiling for real time decisions in cancer treatment

Overview

Ovarian Cancer statistics and treatment

Clearity Foundation: mission and process

Clearity profiling panel and results interpretation

Incorporating profiling in clinical trial designs

22,280 new cases and 15,500 deaths estimated in the US in 2012

~75% diagnosed at stage III/IV

Most treated with surgical cytoreduction followed by adjuvant platinum-taxane based chemotherapy

Most patients recur within 2 years and receive multiple rounds of subsequent chemotherapy

27% survive >10 years

Ovarian cancer statistics and standard of care

Multiple choices for recurrent diseaseCan we inform the treatment decision?

NCCN Guidelines for Epithelial Ovarian Cancer/Fallopian Tube Cancer/Peritoneal Cancer 3.2012

Bring molecular profiling to the forefront of ovarian cancer diagnosis and treatment

Assist doctors in identifying therapy informed by their patient’s tumor molecular profile

Expedite the clinical development of novel targeted agents for ovarian cancer

Increase the probability of success by utilizing molecular profiling to select patients for clinical trials

The Clearity Foundation launched as a non-profit organization in 2008 to:

Leading advisors and scientific presentations

Scientific Advisory Board

Beth Karlan, MD, Chair Cedars Sinai & UCLA Medical Center

Doug Levine, MD Memorial Sloan Kettering Cancer Center

Johnathan Lancaster, MD Moffitt Cancer Center

Julie Cherrington, PhD Pathway Therapeutics

Ursula Matulonis, MD Dana Farber Cancer Center & Harvard Medical School

Deb Zajchowski, PhD Clearity Foundation Scientific Director

6

Mol Cancer Ther; 11(2) February 2012: Treatment-related protein biomarker expression differs between primary and recurrent ovarian carcinomas DA Zajchowski, BY Karlan and LK Shawver

ASCO 2011: Expression Profiles in Matched Primary and Recurrent Ovarian Carcinomas DA Zajchowski, BY Karlan and LK Shawver,

AACR 2011: Molecular Profiling in Recurrent Ovarian Cancer Patients DA Zajchowski, C Bentley, J Gross, BY Karlan and LK Shawver

AACR 2010: Selecting Patients for Ovarian Cancer Clinical Trials by Profiling Tumors against a Broad Panel of Molecular MarkersDA Zajchowski, J Gross, BY Karlan, K Bloom, D Loesch, A Alarcon and LK. Shawver

Ovarian cancers are molecularly heterogeneous

Any one genomic alteration is found in only a small fraction of patient tumors One drug will not be effective for the population Drugs must be developed for specific molecular tumor types Profiling of individual tumors is essential A broad profiling panel is necessary

Serous ovarian cancer

Data provided by Dr. D. Levine

Genomic alterations observed in nearly every chromosome

7

How Clearity works

Patient and medical team using molecular profiles to prioritize therapeutic options

Oncologists and Patients

8

Clearity Profiling Services:• Physician and patient education• Testing coordination• Secure data analysis• Results reported to patient

Use tumor molecular profiles to inform choice of chemotherapy and/or clinical trial

Chemotherapy Marker Panel

Targeted Therapy Marker Panel

Select chemo for combination with targeted agent in

clinical trial

Select chemotherapy

for next treatment

Select clinical trial with targeted

agent9

Key take away messages

Chemotherapy agents are targeted cytotoxic treatments

Chemotherapy will continue to play an important role but molecular targeted agents, on an individualized basis, will become increasingly important

Molecular profiling is available to help prioritize treatments and will be increasingly utilized– for chemotherapy agents– for molecular targeted agents– for clinical trials

Clinical trials should be considered early in the treatment process

* DNA amplification

Growth Factors/ Receptors

EGFR* Her2* IGF1R c-Met* VEGF PDGFR

Cytoplasmic Signal Transducers and Apoptosis Regulators

K-ras** B-raf** PIK3CA** PTEN Bcl-2 Survivin Cox-2

Nuclear Signaling Proteins

Hormone Receptors/Transcription Factors Cell Cycle

ER AR PR Ki67 p16 Rb

Chemotherapy Resistance Markers

Drug Transporters DNA Repair/ Modification DNA Synthesis/Cell Division

BCRP MRP1 MDR1/PGP ERCC1 MGMT RRM1 TS TUBB3

** DNA mutational analysis

Chemotherapy Sensitivity Markers

DNA Synthesis/Transcription ECM

TLE3 Topo1 Top2A SPARC

Current panel of IHC tests

11

*200 patients; March 15, 2012 (n=242; Aug 15, 2012)

UNK3%

I8% II

7%

III76%

IV6%

StageRefractory

7%

Resistant15%

Sensitive53%

NA25%

Platinum Response

Ovary34%

Primary peritoneal

20%

Distant Mets5%

Peritoneal recurrence

41%

Specimen SourceUNK2%

Ad5% CS

1%CC6% Endo

8% GC2% Mucin

2%

MMMT1%

Mixed3%

Serous70%

SB1%

TC1%

Histology

N=244

Data stored and analyzed in Diane Barton Database

Data collected as histoscores

Histoscore = % tumor stained x

Intensity =92

Marker expression in all patients provides basis for interpretation of individual results

Box, inter-quartile range; line, median; whiskers, maximum and minimum values

0

50

100

150

200

250

300

EG

FR

HE

R2

IGF

1Rb

c-M

ET

PD

GF

R A

lpha

PD

GF

R B

eta

VE

GF

CO

X-2 ER

AR

PR

Ki-

67

TO

PO

1

TO

P2A T

S

RR

M1

ER

CC

1

TU

BB

3

TLE

3

PG

P/M

DR

1

SP

AR

C

BC

RP

MR

P1

MG

MT

H S

core

http://www.clearityfoundation.org/drugs-and-biomarkers.aspx

Clinical research evidence for biomarkers is used to interpret results

Low: <25th percentile High: >75th percentile

Low RRM1 Gemzar

High Topo II Doxorubicin, etoposide

High PGP No Taxane, no doxil

High Topo I Irinotecan, topotecan

High SPARC nab-Paclitaxel

Chemotherapy selection uses published evidence and expression cut-offs derived from current database

Low TS Fluoropyrimidines

0

50

100

150

200

250

300

TO

PO

1

TO

P2

A

TS

RR

M1

PG

P

SPA

RC

BC

RP

H S

core

*

High BCRP No Topotecan

17

Case Study: profile for patient diagnosed in 3/2005 with stage IIIB papillary serous carcinoma

Figure 5. Tumor Molecular Profile Informs Therapeutic Decisions

3/2005Carbo/tax x6

taxol 10 mos

recurrence 12/2008 carbo/tax x 6

carbo/tax/bev x3

12/2009Doxil x3

Surgery 1/2010

Tumor Profiled

Gemzar

0

50

100

150

200

250

300

EGFR

HER

2

IGF1

Rb

c-M

ET

PDG

FR A

lpha

PDG

FR B

eta

VEG

F

COX-

2 ER AR PR

Ki-6

7

TOPO

1

TOP2

A TS

RRM

1

ERCC

1

TUBB

3

TLE3

PGP/

MDR

1

SPAR

C

BCRP

MRP

1

MG

MT

H Sc

ore*

18

Case Study: profile for patient diagnosed in 3/2005 with stage IIIB papillary serous carcinoma

Figure 5. Tumor Molecular Profile Informs Therapeutic Decisions

3/2005Carbo/tax x6

taxol 10 mos

recurrence 12/2008 carbo/tax x 6

carbo/tax/bev x3

12/2009Doxil x3

Surgery 1/2010

Tumor Profiled

Gemzar

0

50

100

150

200

250

300

EGFR

HER

2

IGF1

Rb

c-M

ET

PDG

FR A

lpha

PDG

FR B

eta

VEG

F

COX-

2 ER AR PR

Ki-6

7

TOPO

1

TOP2

A TS

RRM

1

ERCC

1

TUBB

3

TLE3

PGP/

MDR

1

SPAR

C

BCRP

MRP

1

MG

MT

H Sc

ore*

High EGFR (98th percentile) EGFR inhibitors have been

ineffective in clinical trials although benefit seen in individual patients

Mutations can predict sensitivity and resistance to EGFR inhibitors in lung cancer

Follow up mutation analysis conducted; patient was wt

19

Case Study: profile for patient diagnosed in 3/2005 with stage IIIB papillary serous carcinoma

Figure 5. Tumor Molecular Profile Informs Therapeutic Decisions

3/2005Carbo/tax x6

taxol 10 mos

recurrence 12/2008 carbo/tax x 6

carbo/tax/bev x3

12/2009Doxil x3

Surgery 1/2010

Tumor Profiled

Gemzar

0

50

100

150

200

250

300

EGFR

HER

2

IGF1

Rb

c-M

ET

PDG

FR A

lpha

PDG

FR B

eta

VEG

F

COX-

2 ER AR PR

Ki-6

7

TOPO

1

TOP2

A TS

RRM

1

ERCC

1

TUBB

3

TLE3

PGP/

MDR

1

SPAR

C

BCRP

MRP

1

MG

MT

H Sc

ore*

High ER Anti-estrogens and aromatase

inhibitors utilized in ovarian cancer patients but not approved due to lack of efficacy in clinical studies

20

Case Study: profile for patient diagnosed in 3/2005 with stage IIIB papillary serous carcinoma

Figure 5. Tumor Molecular Profile Informs Therapeutic Decisions

3/2005Carbo/tax x6

taxol 10 mos

recurrence 12/2008 carbo/tax x 6

carbo/tax/bev x3

12/2009Doxil x3

Surgery 1/2010

Tumor Profiled

Gemzar

0

50

100

150

200

250

300

EGFR

HER

2

IGF1

Rb

c-M

ET

PDG

FR A

lpha

PDG

FR B

eta

VEG

F

COX-

2 ER AR PR

Ki-6

7

TOPO

1

TOP2

A TS

RRM

1

ERCC

1

TUBB

3

TLE3

PGP/

MDR

1

SPAR

C

BCRP

MRP

1

MG

MT

H Sc

ore*

High SPARC Clinical trial for nab-paclitaxel

(none at the time) or off-label use

patient had long history of taxane treatment

21

Case Study: profile for patient diagnosed in 3/2005 with stage IIIB papillary serous carcinoma

Figure 5. Tumor Molecular Profile Informs Therapeutic Decisions

3/2005Carbo/tax x6

taxol 10 mos

recurrence 12/2008 carbo/tax x 6

carbo/tax/bev x3

12/2009Doxil x3

Surgery 1/2010

Tumor Profiled

Gemzar

0

50

100

150

200

250

300

EGFR

HER

2

IGF1

Rb

c-M

ET

PDG

FR A

lpha

PDG

FR B

eta

VEG

F

COX-

2 ER AR PR

Ki-6

7

TOPO

1

TOP2

A TS

RRM

1

ERCC

1

TUBB

3

TLE3

PGP/

MDR

1

SPAR

C

BCRP

MRP

1

MG

MT

H Sc

ore* Low TS

Fluoropyrimidines and pemetrexed considered as a reasonable option

22

Case Study: profile for patient diagnosed in 3/2005 with stage IIIB papillary serous carcinoma

Figure 5. Tumor Molecular Profile Informs Therapeutic Decisions

3/2005Carbo/tax x6

taxol 10 mos

recurrence 12/2008 carbo/tax x 6

carbo/tax/bev x3

12/2009Doxil x3

Surgery 1/2010

Tumor Profiled

Gemzar

0

50

100

150

200

250

300

EGFR

HER

2

IGF1

Rb

c-M

ET

PDG

FR A

lpha

PDG

FR B

eta

VEG

F

COX-

2 ER AR PR

Ki-6

7

TOPO

1

TOP2

A TS

RRM

1

ERCC

1

TUBB

3

TLE3

PGP/

MDR

1

SPAR

C

BCRP

MRP

1

MG

MT

H Sc

ore*

Low RRM High RRM1 associated

with resistance to gemcitabine

Gemcitabine is an approved agent in recurrent ovarian cancer

Drug Mechanism of Action

Gemcitabine Inhibits cell division by blocking DNA synthesis

Gem Gem

RRM1

GemPP-> GemPPP

DCKENT1 RRM2

Blocks DNA

synthesis

Growth inhibition

HuR

dCDP

CDP

1

2

3 4

5

RRM1 is gemcitabine’s target and efficacy biomarker

Gemcitabine Resistance Markers

Marker Name Biological Role Evidence ReferencesRRM1 ribonucleotide

reductase, regulatory subunit

M1

Enzyme synthesizes deoxyribonuceosides from ribonucleoside precursors

High protein levels associated with poor response and outcome in pancreatic, biliary, and NSCLC

patients after gemcitabine-based therapy

Akita, Zheng et al. 2009; Reynolds, Obasaju et al.

2009; Nakamura, Kohya et al. 2010

RRM2 ribonucleotidereductase,

regulatory subunit M2

Enzyme synthesizes deoxyribonuceosides from ribonucleoside precursors

High mRNA expression correlated with poor outcome following

gemcitabine treatment in pancreatic, NSCL, and ovarian

cancer

Itoi, Sofuni et al. 2007; Boukovinas, Papadaki et al.

2008; Souglakos, Boukovinas et al. 2008;

Ferrandina, Mey et al. 2010

For information on each marker, visit http://www.clearityfoundation.org/drugs-and-biomarkers.aspx 23

Ge,zar

24

Case Study: profile for patient diagnosed in 3/2005 with stage IIIB papillary serous carcinoma

Figure 5. Tumor Molecular Profile Informs Therapeutic Decisions

3/2005Carbo/tax x6

taxol 10 mos

recurrence 12/2008 carbo/tax x 6

carbo/tax/bev x3

12/2009Doxil x3

Surgery 1/2010

Tumor Profiled

Gemzar

0

50

100

150

200

250

300

EGFR

HER

2

IGF1

Rb

c-M

ET

PDG

FR A

lpha

PDG

FR B

eta

VEG

F

COX-

2 ER AR PR

Ki-6

7

TOPO

1

TOP2

A TS

RRM

1

ERCC

1

TUBB

3

TLE3

PGP/

MDR

1

SPAR

C

BCRP

MRP

1

MG

MT

H Sc

ore*

Gemcitabine

Gemzar (3/2010)

9/2011: NED

Topo II inhibitors

Gemcitabine Topo I inhibitors

Pemetrexed, capecitabine

Often, only one of the commonly used agents to treat recurrent ovarian cancer is prioritized by the profile

Teal, tumor marker expression met quartile cutpoint criterion: RRM1, TS <25 th percentile; TOP2A, TOP1 >75th percentile.150/196 (76%) can be assigned to one of these agents. 25

Biopsy of recurrent disease is needed to obtain relevant profiling information

26

Mol Cancer Ther; 11(2) February 2012

68% 3+; 2555% 2+; 10

Primary Recurrence

EGFR

Marker expression differences in patient-matched primary and recurrent samples

35SE-O-S

35SE-M-S

10

40

160

EGFR HER2 IGF1Rb c-MET VEGF COX-2 ER Ki-67 TOPO1 TOP2A TS RRM1 ERCC1 PGP SPARC BCRP MRP1 MGMT

H sc

ore

42S-P-S

42S-M-S

42S-MD-S

10

40

160

EGFR HER2 IGF1Rb c-MET VEGF COX-2 ER Ki-67 TOPO1 TOP2A TS RRM1 ERCC1 PGP SPARC BCRP MRP1 MGMT

H sc

ore

Molecular characterization of ovarian tumors reveals new means for targeting and stratifying patients

Advances in methods for genomic characterization of tumor samples (next-gen sequencing in CLIA setting)

Increase in the number of molecularly targeted agents entering trials for ovarian cancer

Our knowledge and ability to rationally target ovarian cancer has evolved since 2008

28

Low frequency of specific genetic aberrations in primary high grade serous ovarian carcinoma

—> extensive genomic interrogation necessary to characterize tumors

From TCGA study: Nature 474, 609- 615 (2011)29

From TCGA study: Nature 474, 609- 615 (2011) 30

Genomic markers can be used to assign patients to clinical trial agents

RB PI3K/RAS

Notch

HR Alterations/BRCAness

CDK inhibitorsAURK inhibitors PI3K/AKT/mTOR inhibitors

MEK inhibitors

Notch inhibitors

PARP inhibitors

New emphasis for profile: clinical trial selection

Chemotherapy Marker Panel

Targeted Therapy Marker Panel (IHC and DNA SEQ)

Select chemo for combination with targeted agent in

clinical trial

Select chemotherapy

for next treatment

Select clinical trial with targeted

agent

31

Expanded panel provides more options for Clearity patients

TaxanesGemcitabine

DoxilTopo I inh

(Pemetrexed)

DNA repair inhibitors Cell cycle inhibitors

Proliferation/survival signaling

inhibitors

GF / ReceptorsEGFR*

Her2*

IGF1R*

c-Met*

VEGF

PDGFR*

ER*

Cell Cycle/ SurvivalPTEN*

Bcl-2*

Cox-2

Survivin

Rb*

P16*

CCND1*

ABL1

CDKN2B

GPR124

MTOR

SMARCA4

ABL2

CDKN2C

GUCY1A2

MUTYH

SMARCB1

AKT1

CEBPA

HOXA3

MYC

SMO

AKT2 CHEK1

HRAS

MYCL1

SOX10

AKT3 CHEK2

HSP90AA1MYCN

SOX2

ALK

CRKL

IDH1

NF1

SRC

APCCRLF2

IDH2

STAT3

AR CTNNB1

IGF1R

STK11

ARAF

DDR2

IGF2R

NOTCH1SUFU

ARFRP1

DNMT3A

NPM1

TBX22

ARID1A

DOT1L

IKZF1

NRAS

TET2

ATM

EGFR

INHBA

NTRK1

TGFBR2

ATR

EPHA3

INSR

NTRK2

AURKA

EPHA5

IRS2

NTRK3 TNKS

AURKB

EPHA6

JAK1

TNKS2

BAP1

EPHA7

JAK2

TOP1

BCL2

EPHB1

JAK3

PDGFRA

TP53

BCL2A1

EPHB4

PDGFRB

TSC1

BCL2L1

EPHB6KDM6A

PHLPP2

TSC2

BCL2L2

ERBB2

KDR

PIK3CAUSP9X

BCL6

ERBB3

KIT

PIK3CG

VHL

BRAF

ERBB4

KRAS

PIK3R1WT1

BRCA1

ERCC2

LRP1B

BRCA2

LRP6

PLCG1

ESR1

PRKDC

CBL

EZH2

MAP2K1

PTCH1

CCND1

FANCA

MAP2K2

PTCH2

CCND2

FBXW7

MAP2K4

PTENCCND3

FGFR1

MCL1

PTPN11CCNE1

FGFR2

MDM2

PTPRD

CD79A

FGFR3

MDM4

RAF1

CD79B

FGFR4

MEN1

RARA

CDH1 FLT1

MET

RB1

CDH2 FLT3

MITF

RET

CDH20 FLT4

MLH1

RICTOR

CDH5 FOXP4

MLL

RPTOR

CDK4GATA1

MPL

RUNX1

CDK6

GNA11

MRE11A

SMAD2

CDK8

GNAQMSH2

SMAD3

CDKN2A

GNAS

MSH6

SMAD4

DNA Repair

Membrane Receptors

PI3K-AKT-MTOR

RAS-MAPK

NF2

NKX2-1

IKBKETNFAIP3

PAK3

PAX5JUN

PKHD1

ERG

CARD11

LTK

Cell Cycle

Plus more…….

Genotype Analysis: Mut/Fusions/Transloc/Amp-Del

BRCAnalysis (DNA Repair/HR Pathway Marker Panel)

Targeted Tx panel

ChemoTx panel

Chemoresistance Markers

Apoptosis Regulators Survivin

DNA Repair/ Modification ERCC1 MGMT

DNA Synthesis/Cell Division RRM1 RRM2 TS TUBB3

Drug Transporters MDR1/PGP BCRP MRP1

Chemosensitivity Markers

DNA Synthesis/Cell Cycle Topo1 Top2A Ki67

Transcription/Translation Regulators TLE3 HuR

Drug Transporters/Metabolism ENT1 DCK

Clinical trial options

IHC

IHC + DNA Seq*

32* Next-gen exon sequencing of 182+ genes

Frequency of hotspot mutations in PIK3CA, KRAS, BRAF, and EGFR is histology-dependent

Clear cell: PIK3CAMucinous and carcinosarcoma: KRAS

Serous Endo CC Muc Ad C (MM) SBPIK3CA WT 82 13 4 2 3 2 1

Mut 1 2 5 0 1 0 0KRAS WT 66 6 2 2 4 1 1

Mut 1 1 0 1 0 2 0BRAF WT 11 2 1 1 1 1 1

Mut 0 0 0 0 0 0 0EGFR WT 10 1 1 3 1 0 0

Mut 0 0 0 0 0 0 0

AMP

AMP

Histology TP53 MDM2 KRAS NF1 CCND1CCND2CCNE1 MYC MYCL1 MYCN BRCA1 BRCA2 ATM IGF1R PATCH CDK4 MCL1 PIK3CA

S MUT FS AMP

S MUT AMP FS AMP AMP AMP AMP

S MUT FS AMP AMP FSS MUT AMP FS AMPS MUTS SSS MUT AMP TRS TR AMPS AMP AMP AMPS AMP AMPS

CC MUTCC* MUT MUT

MX-ECCM MUT MUTMX-ECC MUT

>5-fold

≤5-fold

SS, splice site mutation; FS, frameshift; TR, truncation

Examples of gene alterations in recurrent ovarian cancer

0

50

100

150

200

250

300

HE

R2

EG

FR

CO

X-2

Ki-6

7

ER

PR

AR

TO

PO

1

TO

P2

A

TS

RR

M1

ER

CC

1

BC

RP

MR

P1

MG

MT

PG

P

H S

co

re*

Case Study: profile for patient diagnosed in 2009 with stage IIIC clear cell carcinoma

4/2009CDDP/tax (ip) x 3Carbo/tax (iv) x3

12/2009 recurrence

Tumor profiled

1/2010 Topotecan + AMG 386*

(clinical trial)

5/2011 Stable disease

Topotecan

DNA Sequencing Results

IHC Results

Case Study: profile for patient diagnosed in 2009 with stage IIIC clear cell carcinoma

4/2009CDDP/tax (ip) x 3Carbo/tax (iv) x3

12/2009 recurrence

Tumor profiled

1/2010 Topotecan + AMG 386*

(clinical trial)

5/2011 Stable disease

6/2011 Surgery -- residual disease

RxIrinotecan + Everolimus

0

50

100

150

200

250

300

HER

2

EGFR

IGF1

Rb

c-M

ET

CO

X-2

Ki-6

7 ER PR AR

TOPO

1

TOP2

A

SPA

RC

SPA

RC

TLE3 TS

RR

M1

ERC

C1

TUB

B3

BC

RP

MR

P1

MG

MT

PGP

H S

core

*

Gene Mutation Approved Drugs and Clinical Trial Agents

PIK3CA H1047RPI3K inhibitors, mTOR inhibitors

(rapamycin, temsirolimus, everolimus)

Tumor profiled

9/2012 NED

Irinotecan

Everolimus

DNA Sequencing Results

SUMMARY of AGENTS IHC Results

IHC results—Drug correlations

Protein and DNA results are integrated into one report that highlights therapy options

Clearity report summarizes results from multiple labs and provides consensus interpretation

Summary of relevant patient medical history

Summary of agents (approved and in clinical

trials) associated with clinical benefit extracted

from pg 2

Compilation of data from all labs with interpretation

(percentile rank, potential drugs)

Individual profile compared to ovarian cancer population

Contact information for help with clinical trials, lab reports.

Number of patients whose data are included in Diane

Barton Database

38

New emphasis for profile: clinical trial selection

Chemotherapy Marker Panel

Targeted Therapy Marker Panel (IHC and DNA SEQ)

Select chemo for combination with targeted agent in

clinical trial

Select chemotherapy

for next treatment

Select clinical trial with targeted

agent

39

Vision of an Ovarian Cancer Clinical Trials Coalition (OCCTC)

Increase the probability of drug development success by utilizing molecular profiling to select patients for clinical trials

Facilitate access to eligible patients through patient advocate-driven clinical trials education, outreach, and established web portal for clinical trials identification and matching

Remove barriers for screening large number of patients for enrollment by testing for all drug biomarkers in every patient

Reduce costs of profiling assays and make efficient use of biopsy samples

Make more treatment options available for ovarian cancer patients40

Summary

41

• Ovarian cancer is heterogeneous and a broad profiling panel is needed to capture data relevant to each individual

• Commonly utilized agents for treatment of recurrent ovarian cancer can be prioritized using molecular markers

• Molecular profiling can help prioritize drugs being tested in clinical trials

Thank you!

42

• To everyone who has participated in the Clearity process

• To our physician partners

• To the Clearity team• Dr. Deb Zajchowski• Hillary Theakston• Kathleen Zajchowski• And our volunteers!

www.clearityfoundation.org