Novel&Breast&Cancer&Therapy:& - - PowerPoint PPT Presentation

Novel&Breast&Cancer&Therapy:& Should&we&have&any& cardiovascular&concerns?

Dr.$Chris)ne$Simmons,$MD$MSc$FRCPC$ Medical$Oncologist,$BCCA$Vancouver$ Clinical$Associate$Professor,$Faculty$of$Medicine,$UBC$ Founder$and$Chair,$All$in$Cancer/Women$in$Cancer$

Disclosures

• Honoraria:$Eisai,$Amgen,$Roche,$Novar)s$

$

• Grants:$Roche,$Amgen,$Genomic$Health$
• Research:$Roche,$Amgen,$Novar)s$

Objec?ves

1.$To$summarize$the$main$areas$of$novel$breast$cancer$therapeu)cs$$

• Mechanism$of$ac)on$
• Improvement$in$breast$cancer$outcomes$observed$

2.$To$review$the$current$knowledge$of$cardioStoxicity$of$novel$breast$ cancer$therapeu)cs$

• What$has$been$demonstrated$
• What$has$been$studied$
• What$has$not$been$studied$
• What$further$poten)al$outcomes$could$we$expect$

Novel&Breast&Cancer&Therapy:& Se@ng&the&Stage

• Drug$Development$in$Oncology$
• Inves)ga)onal$new$drugs$are$developed$based$on$poten)al$cyctotoxicity$and$

ini)ally$studied$(usually)$in$cell$lines,$animal$models,$and$then$in$the$ advanced$seWng$

• Phase$I$studies,$“First$in$Human”$studies,$poten)ally$no$further$therapeu)c$op)ons

$$

• Phase$II$studies$(single$arm,$advanced$disease)$
• Phase$III$studies$(randomized$controlled$trials,$usually$in$metasta)c$seWng$to$start)$
• Median$Survival$for$metasta)c$breast$cancer$pa)ent$in$2016$
• Typically$about$2S3$years$(ACS,$ASCO)$
• Improved$to$median$of$26$mos$$from$20$mos$(SEER$registry$2007S2011$vs.$

1988S1991)$

• 5$year$survival$rate$23%,$10$year$survival$rate$5%$

What&does&this&mean?

• Metasta)c$seWng$is$where$novel$therapeu)cs$are$developed$typically$
• Collec)ng$long$term$cardioStoxicity$data$collec)on$is$s)ll$a$hard$sell$in$

this$seWng!$

• Cost$of$trials$
• Pa)ent$engagement$
• Pragma)sm$
• SOOOOO…..$
• There$is$s)ll$a$lot$that$we$don’t$know$and$s)ll$a$lot$to$learn$
• Collabora'on)between)oncology)and)cardiology)is)key)in)trial)development)

Novel&strategies&in&ER+&disease

RESTRICTION$POINT$

CDK&4/6&inhibi?on

$

Cardiac&Concerns

Exclusion$criteria:$

• Clinically$significant,$uncontrolled$heart$disease$and/or$cardiac$repolariza)on$abnormality$

including$any$of$the$following:$

• History$of$myocardial$infarc)on$(MI),$angina$pectoris,$symptoma)c$pericardi)s,$or$coronary$artery$bypass$

graf$(CABG)$within$6$months$prior$to$study$entry$

• Documented$cardiomyopathy$
• Pa)ent$has$a$known$Lef$Ventricular$Frac)on$(LVEF)$<50%$as$determined$by$Mul)ple$Gated$acquisi)on$

(MUGA)$scan$or$echocardiogram$(ECHO).$

• Long$QT$syndrome$or$family$history$of$long$QT$syndrome$or$family$history$of$idiopathic$sudden$death$or$

congenital$long$QT$syndrome,$or$any$of$the$following:$i.$Risk$factors$for$Torsades$de$Pointe$(TdP)$including$ uncorrected$hypokalemia$or$hypomagnesaemia,$history$of$cardiac$failure,$or$history$of$clinically$significant/ symptoma)c$bradycardia$ii.$Concomitant$medica)ons(s)$with$a$known$risk$to$prolong$the$QT$interval$and/or$ known$to$cause$Torsades$de$Pointe$that$cannot$be$discon)nued$or$replaced$by$safe$alterna)ve$medica)on$ (e.g.$within$5$halfSlives$or$7$days$prior$to$star)ng$study$drug)$iii.$Inability$to$determine$the$QTc$interval$

• Clinically$significant$cardiac$arrhythmias$(e.g.,$ventricular$tachycardia),$complete$lef$bundle$branch$block,$

highSgrade$AV$block$(e.g.,$bifascicular$block,$Mobitz$type$II$and$third$degree$AV$block)$

• Corrected$QT$interval$(QTc)$>$480$msec$on$screening$electrocardiogram.$If$QTc$prolonga)on$is$felt$to$be$

related$to$electrolyte$imbalance,$an$EKG$can$be$repeated$afer$correc)on$of$electrolytes.$

BoKom&line

• CDK4/6$inhibitors$double$the$progression$free$survival$of$metasta)c$ER

+Her2S$breast$cancer$pa)ents$

• Likely$will$show$impressive$OS$benefit$as$data$matures$
• These$agents$are$being$used$more$rou)nely$with$access$via$compassionate$

access$programs$given$the$impressive$results$

• But$these$agents$have$been$associated$with$QTc$prolonga)on,$and$current$
• ngoing$studies$exclude$pa)ents$at$risk$for$QTc$prolonga)on$
• ECG$is$NOT$currently$part$of$standard$rou)ne$follow$up$on$metasta)c$

breast$cancer$pa)ents$

Novel&Therapies&in&Her2+&disease

An?MHer2&therapies&in& combina?on

Not$so$much$novel,$as$evolved$ First$line$Trastuzumab+Pertuzumab+Taxane$ now$standard$of$care$ Second$line$TrastuzumabSEmtansine$ $ When/should/how$do$we$monitor$cardiac$ func)on$in$the$metasta)c$seWng?$ What$are$the$implica)ons$of$compromising$ curability$in$the$adjuvant$seWng$for$ asymptoma)c$effects$on$LVEF?$ What$are$the$implica)ons$of$survivorship$ management$for$lower$risk$Her2+$disease?$ $

25.1$ 27$ 50$ 15.6$ 25.5$ 30.9$ 12$

Slamon$ 2001$ Glemon$ 2012$ Baselga$ 2013$ Geyer$ 2006$ von$ Minkwitz$ 2009$ Verma$ 2012$ Blackwell$ 2010$

TDMS1$ First$line$metasta)c$ median$OS$ Second$line$ metasta)c$ median$OS$ 3+$line$ therapy$ Pertuz+$ Tras$+$ chemo$

We&are&ge@ng&beKer….

• Increased$interest$in$studying$agents$with$fewer$poten)al$cardiotoxic$

effects$

• MMS302$is$a$novel,$HER2Stargeted$an)bodySliposomal$doxorubicin$

conjugate$that$specifically$targets$HER2Soverexpressing$cells$

• Preclinical$and$Phase$1$data$suggest$that$MMS302,$as$a$monotherapy$
• r$in$combina)on$with$trastuzumab,$could$be$effec)ve$for$managing$

previously$treated,$anthracyclineSnaïve,$HER2Sposi)ve$breast$cancer$

• Would$allow$for$adequate$an)Sneoplas)c$therapy$without$the$

cardiotoxicity$observed$with$free$doxorubicin$formula)on$

Immunotherapy&in&Breast&cancer

Cardiac&concerns&with&immunotherapy

• Most$common$side$effects$are$related$to$immunotherapy$
• coli)s,$hepa))s,$rash$and$endocrinopathies$
• myocardial$fibrosis$$
• pericardi)s$$
• cardiomyopathy$with$takotsuboSlike$syndrome$induced$by$ipilimumab$
• acute$heart$failure$under$therapy$with$pembrolizumab$
• Currently$only$case$series$
• Single$agent$effec)ve,$but$likely$will$combine$the$other$therapies$in$

future$

• Cardiotoxicity$poten)ally$underes)mated$

Novel&Therapeu?cs&and&Cardiotoxicity:&& S?ll&a&concern

Novel)Area)

ER+$breast$cancer:$

• Cell$cycle$inhibi)on$(CDK4/6$

inhibitors)$

Her2+$disease$

• Mul)San)SHer2$agents$

Triple$nega)ve$breast$cancer$

• Immunotherapy$

Poten'al)Cardiac)concerns)

• QTc$prolonga)on$–$could$poten)ally$

be$severe$when$used$in$general$pop$

• Effects$on$myocyte$contrac)lity,$but$

we’re$geWng$smarter!$

• Poten)al$endocrinopathies$
• Arrhythmia,$Adrenal$insufficiency,$

Myocardi)s,$Pericardi)s$

Thank&you!