2019 Sc ie ntific Re tre a t F rida y, April 26, 2019 Disc o ve ry Wo rld Pa vilio n UT I L I ZI NG GE NE T I C MODE L S F OR CARDI O-ONCOL OGY: GE T T I NG T O T HE HE ART OF T HE MAT T E R Carmen Bergom, MD, PhD Department of Radiation Oncology Medical College of Wisconsin T o g e the r, T a king o n Ca nc e r’ s T o ug he st Cha lle ng e s
RADI AT I ON-I NDUCE D T o g e the r, CARDI OT OXI CI T Y T a king o n Ca nc e r’ s • Radiation therapy received by >50% of all cancer patients T o ug he st Cha lle ng e s – Includes breast cancer patients; >3.5 million U.S. breast cancer survivors in U.S. 2019 • Radiation improves cancer-specific survival, but heart radiation Sc ie ntific Re tre a t can cause long-term toxicity • Relative risk of cardiovascular events in early left-sided breast cancer can be 1.3 or greater – Higher risk with other cardiac risk factors, with cardiotoxicity systemic therapy, and higher doses due to involved lymph nodes – Linear relationship between mean heart dose and major cardiovascular events mc w.e du/ de pa rtme nts/ c a nc e r-c e nte r @ MCWCa nc e rCe nte r
RADI AT I ON-I NDUCE D T o g e the r, CARDI OT OXI CI T Y T a king o n Ca nc e r’ s T o ug he st • Relative risk of fatal cardiovascular events is 2-7 in Cha lle ng e s Hodgkin’s Lymphoma patients who receive radiation 2019 Sc ie ntific • Relative risk of fatal cardiovascular events is 2-6+ in Re tre a t childhood cancer survivors receiving higher cardiac radiation doses mc w.e du/ de pa rtme nts/ c a nc e r-c e nte r @ MCWCa nc e rCe nte r
RADI AT I ON-I NDUCE D T o g e the r, CARDI OT OXI CI T Y T a king o n Ca nc e r’ s T o ug he st • Radiation also plays an integral role in treating Cha lle ng e s advanced lung cancer 2019 • Recent studies show that radiation-induced Sc ie ntific Re tre a t cardiotoxicity could manifest within 2 years of radiation for lung cancer • In lung cancer patients, mortality correlates with mean heart dose, or with the percent of the heart receiving 5 Gy, 30 Gy, or 50 Gy mc w.e du/ de pa rtme nts/ c a nc e r-c e nte r @ MCWCa nc e rCe nte r
GOAL : I MPROVE T HE RAPE UT I C RAT I O T o g e the r, T a king o n Ca nc e r’ s T o ug he st Cha lle ng e s 2019 Sc ie ntific Re tre a t mc w.e du/ de pa rtme nts/ c a nc e r-c e nte r @ MCWCa nc e rCe nte r Adapted from https://www.healthxchange.sg/
ST RAT E GI E S T O MI NI MI ZE RADI AT I ON- T o g e the r, I NDUCE D CARDI OT OXI CI T Y T a king o n Ca nc e r’ s T o ug he st • Mounting evidence suggests that complex genetic Cha lle ng e s modifiers contribute to the risk of radiation-induced 2019 toxicity in cancer patients Sc ie ntific Re tre a t – These genetic modifiers remain largely unknown and poorly understood • We have developed the first genetic model to identify heritable modifiers of radiation-induced cardiotoxicity mc w.e du/ de pa rtme nts/ c a nc e r-c e nte r @ MCWCa nc e rCe nte r
RE SE ARCH PL AN Cardiac Identify Identify Novel Irradiation in Biomarkers that Therapeutic Genetic Animal Predict Normal Targets Models Tissue Toxicity Aim to identify factors that modify normal tissue side effects 2019 Sc ie ntific Re tre a t______T o g e the r, T a king o n Ca nc e r’ s T o ug he st Cha lle ng e s
RE SE ARCH PL AN Cardiac Irradiation in Genetic Animal Models Aim to identify factors that modify normal tissue side effects 2019 Sc ie ntific Re tre a t______T o g e the r, T a king o n Ca nc e r’ s T o ug he st Cha lle ng e s
SS AND BN RAT S USE D T O E XAMI NE NORMAL T I SSUE RADI AT I ON SE NSI T I VI T Y • Data suggested differences in the Sprague Dawley (SD) and Brown Norway (BN) rat strain responses to heart radiation • The PhysGen Database from MCW (pga.mcw.edu) gives physiologic and pathologic parameters for SS (derived from SD) and BN inbred strains • Cardiac phenotypes differed between SS and BN rat strains 2019 Sc ie ntific Re tre a t______T o g e the r, T a king o n Ca nc e r’ s T o ug he st Cha lle ng e s
SS AND BN RAT CARDI AC PHE NOT YPE S • Differences in SS and BN rats for post-ischemic infarct size * *P <0.0001 • Start by testing SS vs. BN radiation responses • If differences in cardiac radiation sensitivity, consomic rat testing (chromosome substitution) may be used to identify genetic variants From pga.mcw.edu
RAT MODE L T O T E ST CARDI AC RADI AT I ON SE NSI T I VI T Y • Treated to 24 Gy with 3 equal fields, AP and 2 laterals, with 1.5 cm circular field Image- • Echocardiograms with strain analysis Guided Heart Radiation performed to assess cardiac function • Baseline • 3 months • 5 months 2019 Sc ie ntific Re tre a t______T o g e the r, T a king o n Ca nc e r’ s T o ug he st Cha lle ng e s
RAT MODE L T O T E ST CARDI AC RADI AT I ON SE NSI T I VI T Y Axial Sagittal Coronal Heart 100 Total Lung Structure Volume (%) Left Lung 80 60 40 20 0 0 5 10 15 20 25 30 35 Dose (Gray)
SS RAT S MORE SE NSI T I VE T HAN BN RAT S T O RADI AT I ON-I NDUCE D CARDI OT OXI CI T Y • Adult female rats given 24 Gy * h e a rt w e ig h t to b o d y ra tio (m g /g ) localized cardiac radiation 6 Normalized Heart Weight • Hearts harvested after 5 months 4 • SS rats had significant cardiac 2 hypertrophy (heart enlargement), while BN rats did not 0 S S C o n t r o l S S + R T B N C o n t r o l B N + R T • Hypertrophy occurs to compensate ( n = 4 ) ( n = 8 ) ( n = 4 ) ( n = 7 ) *P<0.05 for poorer function Reviewed consomic tumor studies and • Consistent with hypothesis PGA to guide which consomic rats to • Consomic studies pursued initially test
CONSOMI C RAT MODE L : SS.BN3 • Consomic rats – Rats with same genetic makeup except one chromosome substituted from another strain BN SS Chrom. 3 Selective Breeding SS.BN3 Chromosome 3 from BN strain
SS/ BN/ SS.BN3 RAT CARDI AC PHE NOT YPE S • Differences in SS and BN post-ischemic infarct size ** * *P <0.0001 • Start by testing SS vs. SS.BN3 consomic cardiac radiation responses • Hypothesis: SS and SS.BN3 rats will respond differently to heart radiation From pga.mcw.edu
CONSOMI C RAT MODE L T O T E ST CARDI AC RADI AT I ON SE NSI T I VI T Y SS.Chr3 Image- Consomic Guided Heart (SS.BN3) Radiation SS • Assess SS.BN3 versus SS normal heart tissue radiation sensitivity • Start with 24 Gy x 1 • Obtain echocardiograms at 0, 3, and 5 months
SS RAT HE ART S MORE SE NSI T I VE T O RADI AT I ON • Amount of fluid in the lungs (pleural effusions) increased in the SS rats after radiation • Fluid can be present due to inflammation or heart failure *P < 0.05
SS RAT S E XPE RI E NCE MORT AL I T Y AF T E R L OCAL I ZE D CARDI AC RADI AT I ON 2019 Sc ie ntific Re tre a t______T o g e the r, T a king o n Ca nc e r’ s T o ug he st Cha lle ng e s
NO SI GNI F I CANT DI F F E RE NCE S I N E CHOCARDI OGRAMS F ROM UNT RE AT E D RAT S SS – No Radiation SS.BN3 – No Radiation
SS RAT HE ART S E XHI BI T SYST OL I C DYSF UNCT I ON VI A E CHOCARDI OGRAM SS – 5 Months Post-Radiation SS.BN3 – 5 Months Post-Radiation • The SS heart exhibits decreased contractility after radiation
SS RAT HE ART S E XHI BI T SYST OL I C DYSF UNCT I ON VI A E CHOCARDI OGRAM • Echocardiogram data End Systolic Volume 0 .8 SS † S S SS.BN3 S S .B N 3 0 .6 E S V m l/k g 0 .4 0 .2 0 .0 0 Mo 3 Mo 5 Mo † P < 0.01 Time After Radiation
SS RAT HE ART S E XHI BI T SYST OL I C DYSF UNCT I ON VI A E CHOCARDI OGRAM • Echocardiogram data End Systolic Volume 0 .8 SS † S S SS.BN3 S S .B N 3 0 .6 E S V m l/k g 0 .4 0 .2 0 .0 0 Mo 3 Mo 5 Mo † P < 0.01 Time After Radiation Ejection Fraction SS 1 0 0 SS.BN3 9 0 † E F % 8 0 7 0 0 1 3 5 † P < 0.01 M o n th s p o s t R T Months Post-RT
SS RAT S HAVE L OWE R ST RAI N ON E CHOCARDI OGRAM Left Ventricular Radial Strain Thickening of Myocardium (%) SS S S SS.BN3 S S .B N 3 # † † P < 0.01 Time After Radiation # P < 0.001
I NCRE ASE D MYOCARDI AL NE CROSI S I N SS RAT S 5 MONT HS AF T E R RADI AT I ON SS control SS + RT 4 * Necrosis 3 Score 2 SS.BN3 control SS.BN3 + RT 1 0 SS SS-BN3 S S S S .B N 3 *P < 0.05
I NCRE ASE D F I BROSI S I N SS RAT S 5 MONT HS AF T E R RADI AT I ON TRICHROME STAINING SS SS.BN3
SS RAT HE ART S MORE SE NSI T I VE T O 5X9 GY F RACT I ONAT E D RADI AT I ON SS Heart to Body Ratio (mg/g) 6 SS.BN3 P=0.037 100 0/10 Percent Survival Percent survival 4 4/11 50 2 P=0.039 0 0 0 1 2 3 4 5 SS SS + RT SS.BN3 SS.BN3 + Months Post RT Control (N=8) Control RT Months Post RT (N=5) (N=6) (N=10) • Male rats also exhibit similar patterns, with SS more sensitive than SS.BN3
HE ART GE NE E XPRE SSI ON CHANGE S AF T E R RADI AT I ON Z-Score • RNA-seq gene expression data – From left ventricle at 1 week Chrom. 3 Candidates after radiation SS SS.BN3 SS SS.BN3
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