TRACO 2019 – Breast cancer and Childhood cancer
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TRACO 2019 – Breast cancer and Childhood cancer


FIRST SPEAKER IS FARRAH ZIA, M.D. FROM GEORGE WASHINGTON UNIVERSITY AND RESIDENCY THERE AND ALSO A HOLY CROSS HOSPITAL THEN SHE CAME TO NCI AS A MEDICAL OFFICER. NOW SHE SEES LOTS OF PATIENTS IN THE WOMEN’S MALIGNANCY BRANCH. BREAST CANCER OVERVIEW PREVENTION DIAGNOSIS TREATMENT, FARRAH.>>THANK YOU, TERRY. IS MY VOICE CARRYING? YOU CAN HEAR ME? OKAY. SO TODAY THE TOPIC IS BREAST CANCER AND IT IS A VAST AREA SO WILL I TOUCH ON PREVENTION DIAGNOSIS AND TREATMENT SO YOU WON’T GET A LOT IN A SPECIFIC AREA, KIND OF AN OVERVIEW LECTURE. SO WE’LL START BY WHAT IS BREAST CANCER? THE BREAST AS YOU CAN SEE HERE IS COMPOSED MAINLY OF FATTY TISSUE, BUT WITHIN THE FATTY TISSUE THERE’S AN ENTRY KIT NETWORK OF Q. BULLS AND DUCTS WHICH CARRIES MILL TO BE THE NIPPLE AND WITHIN THE LOBULES AND DUCTS THAT THE MAJORITY OF BREAST CANCER ARISE. ALSO WITHIN THE FATTY TISSUE YOU HAVE BLOOD VESSELS AND LYMPHATIC VESSELS. THE PRECISE REASONS A WOMAN DEVELOPS BREAST CANCER ARE DIFFICULT TO SPECIFY BUTT’S A COMBINATION OF GENETIC ENVIRONMENTAL AND LIFESTYLE FACTORS AND WE KNOW HORMONES HAVE AN IMPORTANT ROLE IN DEVELOPING SPECIFIC HORMONE RECEPTOR POSITIVE BREAST CANCERS. SOME OF THE KNOWN RISK FACTORS ARE AGE BUT MAJORITY ARISE IN POST MENOPAUSAL WOMEN. ALSO IF A WOMAN HAD A PRIOR BREAST CANCER THAT DEFINITELY PUTS HER AT A HIGHER RISK TO DEVELOP A SECOND BREAST CANCER. ALSO WOMEN HAVE A HISTORY OF BENIGN BREAST CONDITIONS WITH OR WITHOUT ATIPIA. THAT ALSO PUTS THEM AT HIGHER RISK. AND EXPOSURE TO EXCESS ENDOGENOUS OR EXOGENOUS HORMONES THROUGH EARLY MENOPAUSE, USE OF HORMONE REPLACEMENT THERAPY, FELONY WOMAN HAD NO PREGNANCIES UNTIL AGE 35 OR OLDER. THAT’S INTERESTING NOBODY UNDERSTANDS REALLY WHY, THAT’S BECAUSE BECAUSE YOUR BREAST — DON’T MATURE UNTIL YOUR FIRST PREGNANCY SO THEY’RE VULNERABLE TO THE EFFECT OF HORMONES. ALSO RAID YEAR AGO EXPOSURE BEFORE AGE 40 FOR EXAMPLE WOMEN, WE HAVE SEEN BREAST CANCER DEVELOPING IN THOSE PATIENTS. ALSO IF YOU HAVE DENSE BREAST TISSUE ON MAMMOGRAM, WHAT IS THE REASON FOR THAT? SO YOU ARE AT HIGHER RISK OF DEVELOPING BREAST CANCER. THE DENSE BREAST TISSUE ALSO, IT’S A LITTLE HARD TO VISUALIZE LESIONS NECESSARILY ON IT INCREASES ESTROGEN LEVELS AND INCREASES DNA DAMAGE, LACK OF EXERCISE IS A RISK FACTOR, EXERCISE CONSUMESES BLOOD SUGAR AND LIMITS INSULIN GROWTH FACTOR WHICH IS A HORMONE THAT CAN AFFECT BREAST CELL GROWTH. OBESITY ALSO IS A RISK FACTOR BECAUSE THERE’S EXTRA FAT CELLS AND THAT’S MORE ESTROGEN IN THE BODY. IT ARISES FROM GENE MUTATION, THERE’S TWO TYPES, GERM LINE MUTATIONS, ARE PRESENT IN THE EGG OR SPERM AND CAUSE HER RED TEAR CANCER SYNDROMES, THEY PASS FROM PARENT TO CHILD THIS IS A CAUSE OF FIVE TO TEN% BREAST CANCER. AND THEN THERE ARE SOMATIC MUTATIONS WHICH OCCUR IN NON-GERM LINE TISSUES. THEY ARE NON-INHERITABLE THEY ARE THE RESULT OF NATURAL AGING PROCESS OR EXPOSURE TO ENVIRONMENTAL CARCINOGENS. YOU CAN SEE A REPRESENTATION OF FREQUENCY OF GENE MUTATIONS IN BREAST CANCER PATIENTS IN A COHORT OF NORTH AMERICAN WOMEN N. IN BLUE YOU SEE ABOUT — REPRESENTATIVE BRACA 1, ORANGE IS BRACA 2, THAT MAKES MAJORITY OF BREAST MUTATIONS. HOWEVER, THERE ARE OTHER GENES AND MAJORITY ARE IN — INVOLVED IN DNA REPAIR. AND THERE ARE ALSO SOME TUMOR SUPPRESSER GENES. IT SHOULD BE NOTED IF YOU HAVE A BRACA MUTATION YOU HAVE UP TO 72% LIFETIME RISK OF DEVELOPING BREAST CANCER. AND P53 IS TUMOR SUPPRESSER GENE, THE CANCER RISK IS NEARLY 100%. SO THE AMERICAN CANCER SOCIETY SAYS THAT IN UNITED STATES WOMEN HAVE 12.4% RISK OF DEVELOPING INVASIVE BREAST CANCER AND MEN WILL HAVE A 0.1% LIFETIME RISK. THE PREDICTIONS FOR 2019 ARE THAT 268,000 CASES OF NEW INVASIVE BREAST CANCER WILL BE DIAGNOSED AND 41,760 WOMEN WILL DIE IN 2019 OF THEIR DISEASE. THAT IS A HUGE NUMBER. AS FAR AS NEW CASES DIAGNOSED WREST CANCER IS ACTUALLY SECOND TO SKIN CANCER, ONLY SECOND TO SKIN CANCER, MORTALITY IT’S ONLY SECONDS TO LUNG CANCER. SO THE INCIDENCE HAS BEEN RISING. INCIDENCE OF BREAST CANCER HAVE BEEN STEADILY INCREASING BASICALLY SINCE THE 1970s. THAT ACTUALLY CAN BE ATTRIBUTED BECAUSE THERE HAS BEEN A STRONGER PUSH FOR SCREENING SO IT’S MAINLY EARLY DETECTION THAT’S LIKELY CAUSING THE THEN AROUND 2000 THERE WAS A SLIGHT DECREASE IN THE INCIDENCE THEORETICALLY DUE TO THE FACT THAT’S THE TIME THE WOMEN HEALTH INITIATIVE STUDY WAS REPORT AND WE REALIZED THAT GIVING HORMONE REPLACEMENT THERAPY WAS A RISK FOR BREAST CANCER. SO THAT WAS SOMETHING COMPLETELY ELIMINATED AND THERE WAS A SLIGHT DECREASE THE MORTALITY RATE IS DECLINING, LIKELY DUE TO ADVANCES IN TREATMENT, EARLY DETECTION AND INCREASED AWARENESS. SO LOOKING AT INCIDENTS AND MORTALITY BY RACE. FOR WHITE FEMALES AND AFRICAN AMERICAN FEMALES THERE WAS A STEADY SHARP RISE IN THE INCIDENCE WHICH IS DEPICTED ON THE TOP GRAPH. THE INCIDENCE HAS ALWAYS BEEN HIGHER FOR WHITE FEMALES. THERE WAS A PLATEAU TOWARD THE END AROUND — BETWEEN 2005 AND 2010. BUT AGAIN WHITE FEMALES ARE STILL AT MUCH HIGHER INCIDENCE. THE MORTALITY IS DECLINING FOR BOTH BUT IT CAN BE NOTED THAT AFRICAN AMERICAN FEMALES UNFORTUNATELY STILL HAVE HIGHER MORTALITY RATE. SO OCTOBER IS BREAST CANCER AWARENESS MONTH SO SINCE I DO THE LECTURE THIS MONTH I LIKE TO TOUCH ON EARLY DETECTION. I WANT TO SAY MAMMOGRAMS SAVE LIVES. I CANNOT STRESS THAT ENOUGH. MAMMOGRAMS CAN BE USED AS SCREENING TOOLS TO DETECT CANCER WHEN THERE ARE NO SYMPTOMS INVOLVED. ALSO USED TO DETECT AND DIAGNOSE BREAST DISEASE BREAST CANCER WHEN A WOMAN IS HAVING SYMPTOMS. IT REDUCES MORTALITY BY 26% IN THE OLDER AGE GROUP, 50 TO 74 AND 17% IN THE AGES 40-49. THE MAJORITY OF BREAST CANCER ARE ACTUALLY DIAGNOSED AFTER MENOPAUSE THAT,s THE REASON FOR THAT DISCREPANCY. THE GUIDELINES RIGHT NOW FOR WOMAN WHO IS AT AVERAGE RISK FROM AGE 40 TO 44, WOMEN HAVE THE CHOICE TO BEGIN ANNUAL MAMMOGRAMS FROM 45 TO 54, THE AMERICAN CANCER SOCIETY DOES RECOMMEND IT. 55 AND OLDER THEY HAVE THE OPTION OF SWITCHING TO BIANNUAL BUT IT DEPENDS AGAIN ON RISK AND FAMILY HISTORY AND ALL THOSE THINGS HAVE TO BE TAKEN INTO CONSIDERATION. FOR WOMEN CONSIDERED HIGH RISK THE RECOMMENDATION FROM THE AMERICAN CANCER SOCIETY WOULD BE AN ANNUAL MRI AND MAMMOGRAM SO IN COMBINATION. AND HIGH RISK IS DETERMINED BY USING SOME SORT OF RISK ASSESSMENT TOOL THAT TAKES MULTIPLE FACTORS INTO CONSIDERATION AND FOR THOSE WOMEN WHO USING THOSE TOOLS IF THEY HAVE GREATER OR EQUAL TO 25% RISK OF DEVELOPING — LIFETIME RISK OF DEVELOPING CANCER. SO JUST SOME NOTES ABILITY THE MRI — ABOUT THE MRI AND USE IN EARLY DETECTION. WHILE MRI IS MORE SENSITIVE THAN MAMMOGRAM, IT ALSO HAS A HIGHER FALSE POSITIVE RATE, THAT MAY NEED TO UNNECESSARY BIOPSIES AND OTHER PROCEDURES. THAT IS WHY THE AMERICAN CANCER SOCIETY DOES NOT RECOMMEND IT FOR THOSE IN THE LOW OR MODERATE RISK GROUP AND ONLY FOR THOSE WOMEN WHO ARE IN THE HIGHER RISK GROUP. COUPLE OF NOTES ABOUT THE CLINICAL BREAST EXAM AND SELF-BREAST EXAM, THIS IS VERY INTERESTING, THERE IS NO SOLID CLINICAL TRIAL EVIDENCE THAT A PHYSICAL BREAST EXAM DONE BY PHYSICIAN OR BY WOMEN THEMSELVES PROVIDES ANY CLEAR BENEFIT IN EARLY DETECTION OR REDUCING BREAST CANCER MORTALITY. SO BECAUSE OF THIS TECHNICAL LACK OF EVIDENCE, REGULAR CLINICAL BREAST EXAMS AND BREAST SELF-EXAMS ARE NOT PART OF THE ACS GUIDELINES. BECAUSE GUIDELINES ARE USUALLY DEVELOPED ACCORDING TO THEIR EVIDENCE BASED GUIDELINES. I WANT TO STRESS DESPITE THAT SURGEON, ALL PHYSICIANS, ALL MEDICAL ONCOLOGISTS WE ALL FEEL THAT CLINICAL BREAST EXAMS ARE EFFECTIVE WHEN YOU LOOK AT EACH INDIVIDUAL RATHER THAN THE MAP IS. SO ALL WOMEN I BELIEVE SHOULD BE FAMILIAR WITH HOW THEIR BEST LOOK AND FEEL AND THEY SHOULD REPORT ANY CHANGES TO THEIR POSITION. I THINK THIS IS IMPERATIVE IN EARLY DETECTION. SINCE THIS IS BREAST CANCER AWARENESS MONTH, THIS IS THE SELF-BREAST EXAM, SOME LIKE TO DO IT ON A MONTHLY BASIS CORRELATING WITH THEIR MENSTRUAL CYCLE SO THAT’S HOW THEY DON’T FORGET. FIRST STEP STANDS STRAIGHT LOOK IN THE MIRROR SHOULDERS STRAIGHT ARMS ON HIPS AND LOOK AT ANY CHANGES IN SIZE SHAPE COLOR DIM LING PUCKERING RETRACTION. YOU WOULD KNOW A CHANGE. SAME THING WITH YOUR ARMS OVER YOUR HEAD. THEN YOU DO IT LYING DOWN, USE A FIRM SMOOTH TOUCH, DOESN’T MATTER HOW YOU DO IT JUST WANT TO CHECK ALL AREAS AND FOLLOW A PATTERN AND COVER THE WHOLE BREAST. THAT’S ALL. THEN YOU DO THE SAME THING WITH THE — YOUR STANDING UPRIGHT WITH YOUR ARMS ABOVE YOUR HEAD SO YOU CAN FEEL FOR THE LYMPH NODE AREA AS WELL. SO WHEN A WOMAN IS DIAGNOSED WITH BREAST CANCER IT IS DEFINITELY A JOURNEY, A JOURNEY THAT TAKES YOU TO MANY STOPS. FIRST ABNORMALITIES DETECTED, EITHER ON SELF-BREAST EXAM BY PHYSICIAN, PATIENT THEMSELVES OR BREAST IMAGING SOMETHING IS NOTED. SO THE NEXT STEP WOULD BE TO HAVE I GUESS BIOPSY BUT A BIOPSY THAT IS A FINE NEEDLE ASPIRATION OR CORE BIOPSY USING A NEEDLE. IT CAN BE IMAGE GUIDED IF NOT PALPABLE. AFTER THAT WE GET PATHOLOGY, INITIAL PATHOLOGY AND THEN PATIENT GOES FOR SURGICAL CONSULTATION. THEN SO HERE SOMETIMES WE GIVE NEOADJUVANT CHEMOTHERAPY WHICH IS CHEMOTHERAPY BEFORE SURGICAL PROCEDURE IS DONE. SOMETIMES IF THE BREAST IS TOO LARGE AND WE SHRINK IT WE’LL GET CHEMOTHERAPY BEFORE SURGERY. MORE OFTEN THAN NOT THE PATIENT GOES TO SURGEON, HAVE A SURGICAL PROCEDURE WHICH COULD BE A LUMPECTOMY, A WIDE E SIGNATURES OF AREA WHERE THE MOUSE IS, IF NOT PALPABLE IT’S A WIRE LOCALIZED EXSIGNATURES WHERE THE INTERVENTIONAL RADIOLOGIST WILL PLACE A WIRE USING IMAGE GUIDED TECHNIQUES AND SURGEON KNOWS WHERE TO GO WHEN THEY GO IN AND EXCISE THE AREA OR A FULL MASTECTOMY. LYMPH NODE RESECTION, THERE’S TWO OPTIONS YOU CAN HAVE A SENTINEL NODE DESECTION OR AX LAYER NODE DESECTION. THESE ARE THE NODES IMPORTANT IN BREAST CANCER, YOU HAVE THE AX LAYER CHAIN, THE MOST IMPORTANT, THEN SUPER CLAVICULAR AREA, SUB CLAVICULAR AREA, THE MEDIASTINAL NODES AND INTERNAL MAMMARY NODES. SO WHEN BREAST CANCER BECOMES INVASIVE IT BREAKS THROUGH THE DUCT OR LOBULES WHERE IT BEGINS MOVES TO THE TISSUE SURROUNDING THE STROMA, THEN ACCESS TO THE LYMPHATIC SYSTEM AND TRAVEL TO OTHER PARTS OF THE BODY. SO LYMPH NODE SAMPLING, THERE’S TWO METHODS SENTINEL NODE OR DISSECTION. SENTINEL IS LESS INVASIVE. IT IS THE CURRENT RECOMMENDATION FOR PATIENTS WITH EARLY STAGE BREAST CANCER WHO ARE CLINICALLY NODE NEGATIVE MEANING WE ARE NOT ABLE TO ACTUALLY PALPATE OR FEEL POSITIVE NODES. WHEN WE EXAMINE THE PATIENT. DURING SURGERY, EYE SILL SAW FAN BLUE IS INJECTED UNDER THE NIPPLE, THE TRACER IS MIXED WITH FLUID AND TRAVEL TO THE LYMPH NODE AND THE SENTINEL NODE IS THE FIRST NODE OR FIRST GROUP OF NODE THAT THAT RECEIVE THE DRAINAGE, THOSE ARE THE NODES TAKEN OUT. THE IDEA IS IF THOSE NODES ARE CLEAN THEN SUBSEQUENT NODES SHOULD BE CLEAN. THE FULL AX LARRY DISSECTION, YOU ARE LOOKING AT THE NODES AND YOU ARE VERY CLEAR THERE IS NOT SPREAD OF THE CANCER, DOWN SIDE IS POST SURGICAL LYMPHODEE MA, INFECTIONS, NERVE DAMAGE AND IT HAPPENS TOO OFTEN. IT WOULD HAVE BEEN NICE TO HAVE A PICTURE TO SHOW YOU BUT IT’S VERY PROBLEMATIC FOR PATIENTS. AFTER SURGERY YOU HAVE THE FINAL PATHOLOGY REPORTS AND THEY GO SEE A RADIATION ONCOLOGIST TO GET A FINAL PLAN. TO MAKE THE FINAL PLAN YOU HAVE TO KNOW STAGE. STAGING IS AN IMPORTANT TOOL TO DETERMINE THE PROGNOSIS AND TO DETERMINE HOW YOU ARE GOING TO TREAT PATIENTS. SO I WON’T GO THROUGH EVERYTHING HERE BUT STAGE ZERO IN BREAST CANCER IS KNOWN AS CARCINOMA IN SITU, IT’S NOTS GONE PAST DUCTS OR LOBULES, STAGE 1 TO 3 ARE BASED ON BASICALLY THE TNM SYSTEM, T IS SIZE OF THE TUMOR, AND IS WHETHER THE NODES ARE POSITIVE AND HOW MANY ARE POSITIVE SEASONED WHETHER THERE IS DISTANT METASTASIS OR NOT. YOU CAN LOOK IN YOUR HAND-OUT. BUT STAGE 4 AS WE KNOW, THAT SADLY WHEN THE CANCER HAS SPREAD TO DISTANT SITES IN THE BODY. IT’S NOT CURABLE BUT THESE DAYS WE HAVE GOOD TREATMENTS AND PATIENTS CAN DO WELL FOR QUITE SOME TIME BUT FOR BREAST CANCER IS MOST COMMON AREAS OF SPREAD ARE THE BONES, THE LUNGS, THE LIVER, THE CHEST WALL OR THE BRAIN. I WANT TO MENTION INFLAMMATORY BREAST CANCER, IT’S A VERY DIFFERENT ENTITY. SO IT’S A RARE FORM OF BREAST CANCER, ITS INCIDENCE IN U.S. IS ONE TO FIVE PERCENT. BUT THIS MAY BE UNDERESTIMATED BECAUSE IT’S VERY DIFFICULT TO TRACK BECAUSE THERE’S VARIATIONS IN DIAGNOSTIC CRITERIA. AND SOMETIMES IT’S MISDIAGNOSED. BUT OFTEN TIMES YOU WILL SEE MALIGNANT CELLS INFILTRATE AND CLOG THE DERMAL LYMPHATICS, HOWEVER, TO BE CLEAR, DERMAL LYMPHATIC INVASION IS NOT A DIAGNOSTIC CRITERIA FOR INFLAMMATORY BREAST CANCER, YOU CAN ACTUALLY SEE THAT IN ANY BREAST CANCER BUT THE DIAGNOSIS IS MAINLY THE CLINICAL PRESENTATION OF HOW THE PATIENT — HOW THE BREAST LOOKS, AND THE FACT YOU HAVE A BIOPSY THAT CONFIRMS THERE IS INVASIVE BREAST CANCER. SO A PATIENT WHO HAS INFLAMMATORY BREAST CANCER I WILL SHOW YOU A PICTURE IN A MINUTE, BUT NORMALLY SEE A RAPID ONSET OF CHANGES IN THE BREAST OVER THREE TO SIX MONTHS. THERE’SER THREE MA THAT COVERS AT LEAST A THIRD OF THE BREAST AND THERE IS EDEMA GIVING THE SKIN AN ORANGE PEEL. AND YOU SEE BREAST ENLARGEMENT BUT NO MASS TO PALPATE BECAUSE THIS IS AN AFRICAN AMERICAN FEMALE YOU CAN SEE THE ERYTHEMA, THE ORANGE APPEARANCE OF THE SKIN BUT YOU CAN SEE HOW THIS MAY GET MISSED AS DIAGNOSIS FOR BREAST CANCER. THERE’S OR VARIED PRESENTATIONS, THESE WERE PATIENTS OF OURS AT THE CLINICAL CENTER. SO YOU CAN SEE, LIKE THE TOP MAY BE LOOKS MORE LIKE INFECTION, THE BOTTOM SOMEBODY MAY SAY IT’S A RASH. SO THESE THINGS WHEN PATIENTS GO IN, WHEN A PATIENT PRESENTS WITH INFLAMMATORY BREAST CANCER AND THEY GO SEE THEIR PRIMARY CARE PHYSICIAN, OFTEN TIMES IT GOES ON FOR SOME TIME BECAUSE LIKELY IT’S NOT FIRST DIAGNOSED AT BREAST CANCER. SOMETIMES IT CAN EVOLVE IF A PATIENT HAD BREAST CANCER AND THINGS CAN EVOLVE INTO INFLAMMATORY PICTURE. OKAY. SO BACK TO JUST TREATMENT DECISIONS. BREAST CANCER IS COMMONLY TREATED WITH VARIOUS COMBINATIONS OF SURGERY, RADIATION THERAPY, CHEMOTHERAPY, HORMONE THERAPY AND TARGETED THERAPY. SO WHAT ARE THINGS WE USE TO MAKE OUR DECISIONS. PROGNOSIS AND SELECTION OF THERAPY, WE USE THESE CLINICAL FACTORS. WHETHER THE PATIENT IS NOW MENOPAUSAL, WHAT IS THE STAGE OF THE DISEASE AS I PREVIOUSLY SAID. THE GRADE OF THE TUMOR, HOW AGGRESSIVE IS IT, HORMONE RECEPTOR STATUS, HER 2 STATUS. HISTOLOGICAL TYPE, PATIENT AGE, CAN THEY TOLERATE CHEMO. BUT NOW A HUGE THING IS MOLECULAR PROFILING. SO THAT TELLS US PRESENCE OF MUTATIONS. I WILL TALK MORE ABOUT THAT LATER. SO THIS IS A CLASSIC GRAPH FROM THE EARLY BREAST CANCER TRIALIST GROUP THAT WAS PRINTED PRINTED
IN THE LANSETT IN 2005. SO PATIENTS WHO ARE — WHO RECEIVE POLYCHEMOTHERAPY, SHOWING BENEFIT OF POLYCHEMOTHERAPY POLYCHEMOTHERAPY IS BASICALLY TREATING BREAST CANCER WITH MORE THAN ONE CHEMO THAT TARGETS DIFFERENT MECHANISMS. THAT’S NORMALLY HOW WE DO IT IN ADJUVANT SETTING WHEN PATIENT IS FIRST DIAGNOSED AND THEY HAVE EARLY STAGE BREAST CANCER, WE ALWAYS TREAT WITH MORE THAN ONE REGIMEN, OUR AT THAT TIME IS TO CURE. WHEN THE PATIENT BECOMES STAGE 4 AND METASTATIC, THAT’S WHEN WE TRY TO USE SINGLE AGENTS BECAUSE AT THAT POINT PAILIATIVE TREATMENT, WE ARE TRYING NOT TO GIVE THE PATIENT TOO MANY TOXICITIES AND WE ALSO WANT TO KEEP OUR ARSENALS IN HAND AND NOT USE TOO MANY THINGS AT ONE TIME. IN THE ADJUVANT SETTING THERE’S ABSOLUTE RISK REDUCTION OR RELAPSE IN MORTALITY WITH POLYCHEMOTHERAPY AND THE RECURRENCE YOU SEE IN THESE GRAPHS IS ON THE LEFT, MORTALITY IS ON THE RIGHT. THE TOP ONE IS YOUNGER WOMEN LESS THAN 50 YOU CAN SEE DIFFERENCE BETWEEN THE CONTROL AND THE POLYCHEMOTHERAPY ARM AND YOU CAN SEE THE YOUNGER PEOPLE HAVE GREATER BENEFIT. THESE ARE EXAMPLES OF THE CHEMOTHERAPIES USED TO TREAT INVASIVE DUCTILE CARCINOMA. FIRST THREE ARE AL DILATING AGENTS, DOCETAXEL, PACK CASH FLOW TACK SOLVE ARE MICROTUBULIN HUBS TO. THE REST ARE ANTI-METABOLITES SO THEY HAVE DIFFERENT MECHANISMS AND WE COMBINE THEM BASED ON DIFFERENT MECHANISMS. THESE ARE EXAMPLES OF HORMONE THERAPIES APPROVED EARLY STAGE LOCAL BREAST CANCER. TAMOXIFEN IS THE OLDEST TRIED AND TRUE. IT’S SELECTED ESTROGEN RECEPTOR MODULATOR WHICH MEANS IT ACTS AS AN ANTAGONIST IN THE BREAST BUT ACTS AS A PARTIAL AGONIST IN THE ENDOMETRIAL. SO THERE IS A SLIGHT RISK OF ENDOMETRIAL CANCER WITH THAT. LETRAZOL AND METHANE ARE AROMATASE INHIBITORS USED IN POST MENOPAUSAL WOMEN. THEY ACT BY BLOCKING THE AROMATASE WHICH IS AN ENZYME THAT CONVERTS OTHER HORMONES TO ESTROGEN. FULLBESTRENT IS AN ANTI-ESTROGEN AND (INDISCERNIBLE) INDUCE OVARIAN SUPPRESSION. SO THEY BLOCK ESTROGEN PRODUCTION FROM THE OVARIES IN PRE-MENOPAUSAL WOMEN. SO SOMETIMES WE CAN USE THIS, WE CAN USE OVARIAN SUPPRESSION AND PUT PATIENTS ON AROMATASE INHIBITOR TO — WHEN THEY ARE PRE-MENOPAUSAL. SO THIS IS ALSO A VERY CLASSIC GRAPH FROM THE LANSETT IN 2005, EARLY BREAST CANCER TRIALIST GROUP SHOWING THE BENEFIT OF TAMOXIFEN IN HORMONE RECEPTOR POSITIVE PATIENTS AS THE ADJUVANT TREATMENT. YOU CAN SEE MOST OF THE GRAPH TO LEFT IS SHOWING BENEFIT FOR RECURRENCE AND THE RIGHT IS SHOWING BENEFIT ON MORTALITY BREAST CANCER MORTALITY, THE MOST EFFECT ON RECURRENCE IS IN THE FIRST FIVE YEARS. AND MOST OF THE EFFECT ON MORTALITY COMES AFTER THE FIRST FIVE YEARS. THERE’S DEFINITELY HUGE BENEFIT FOR HORMONE RECEPTOR POSITIVE PATIENTS TO UTILIZE HORMONE RECEPTOR ADJUVANT THERAPY. EITHER WITH CHEMOTHERAPY OR FOLLOWING CHEMOTHERAPY. MORE RECENTLY WE KNOW OTHER HORMONE THERAPIES DEVELOPED WE KNOW THERE IS GREATER BENEFIT TO SEEK WITH THE SAME HORMONAL THERAPIES. IN THE POST MENOPAUSAL WOMEN WE KNOW FIVE YEARS OF TAMOXIFEN AND THEN FIVE YEARS OF AROMATASE INHIBITOR IS MORE BENEFICIAL THAN TEN YEARS OF TAMOXIFEN. SO THAT IS ON RECURRENCE AND MORTALITY. THESE ARE EXAMPLES OF TARGETED THERAPIES, THE LIST GROWS EVERY YEAR I DO THIS LECTURE. I USED TO TALK EACH INDIVIDUAL ONE AND AS THE YEARS GO ON I HAVE MAKE A CHART BECAUSE THERE’S SO MANY. SO TRASTUZIMAB IS A MONOCLONAL ANTIBODY THAT BINDS SELECTIVELY TO THE HER 2 PROTEIN AND SUPPRESSES ACTIVITY THAT LEADS TO CELL PROLIFERATION, TRASTUZIMAB BINDS TO THE EXTRA CELLULAR DOMAIN OF HER-2 AND IT HINTS LIGAND HER 2 HER 3 DIMERIZATION AND REDUCES SIGNALING THROUGH PI 3 AKT PATHWAY. AMANTASINE IS A COMBINATION OF HERCEPTIN BOUND TO AMANTHASINE SO IT DELIVERS IT TO CANCER CELLS IN A TARGETED WAY ON FOR PATIENTS WHO ARE HER-2 POSITIVE. WILL PAT ANYBODY IS TYROSINE KINASE INHIBITOR, (INDISCERNIBLE) IS MTOR INHIBITOR. CYCLIC ARE ALL THREE CDK 4 INHIBITORS, THEY INDUCE G1 ARREST AND CELL CYCLE DOES NOT PROGRESS. THAT’S THEIR MECHANISM. THEY ARE ACTUALLY ALL OF THEM ARE APPROVED IN COMBINATION WITH AN ENDOCRINE THERAPY, MOST OF THEM WITH PURE (INDISCERNIBLE). OLAPERIB IS A PARP INHIBITOR, TELAZOPERIB IS A TARP INHIBITOR. PARP INHIBITORS HAVE NOT HAD THE BEST OF LUCK IN BREAST CANCER BUT THESE ARE TWO THAT HAVE BEEN RECENTLY APPROVED. THEY ARE APPROVED IN BRACA MUTATED BREAST CANCER BECAUSE BRACA HELPS IN DNA REPAIR AND THE PARP ENZYMES ALSO ARE DNA REPAIR ENZYMES. SO WHEN YOU KNOCK OUT BOTH OF THEM, THEN THEY ARE EFFECTIVE IN CAUSING CELL DEATH. THIS IS ONE I ADDED TO MY LIST. THIS IS A FIRST IN CLASS APPROVAL. THIS WAS JUST APPROVED IN MAY. THIS IS, IT INHIBITS PIC 3 IN THE PI 3 KINASE SIGNALING PATHWAY, INHIBITING THE PATHWAY ACTIVATION. SO THIS IS A COMPLETELY NEW DRUG CLASS. A LOT OF SIDE EFFECTS DEFINITELY I USED IT RECENTLY IN SOME PATIENTS AND LOT OF DIARRHEA AND A LOT OF HYPOGLYCEMIA. A LOT OF SIDE EFFECTS THAT ARE HARD TO MANAGE ACTUALLY. SO HOW DO CLINICIANS MAKE WELL INFORMED DECISIONS ABOUT WHICH PATIENTS TO TREAT WITH CHEMO? AND WHAT TO CHOOSE? WHILE TREATING PATIENTS IN THE GENOMICS ERA CHANGED QUITE A BIT, NOT ONLY DO WE SELECT CHEMOTHERAPY REGIMENS FOR PATIENTS WE ALSO SELECT PATIENTS FOR CHEMOTHERAPY REGIMENS WHICH IS GOOD. NOT ONLY LOOKING AT THE CLINICAL INDICATORS AS I MENTION UP THERE. BUT WE USE GENE EXPRESSION PROFILING TO PREDICT RESPONSE TO PARTICULAR AGENTS AND VERY IMPORTANTLY, USE GENE EXPRESSION PROFILING OF THE PRIMARY TUMOR TO PREDICT AND TREAT ONLY THOSE PATIENTS LIKELY TO RECUR AND WHO WILL THEREFORE BENEFIT FROM ADDITIONAL CHEMOTHERAPY. SO THESE ARE ASSAYS THAT ARE ACTUALLY APPROVED BY INSURANCES AND WIDELY USED NOW. SO JUST IN CASE SOMEBODY IS CONFUSED, WHAT IS THE DIFFERENCE BETWEEN GENOMIC AND GENETIC TESTING? GENETIC TESTING INVOLVES SEQUENCING A PERSON’S DNA USING BLOOD OR SALIVA, GENOMIC IS MORE TERMINOLOGY SO PEOPLE DON’T GET CONFUSED. GENOMIC TESTING ANALYZES THE ACTUAL TISSUE TESTING ITSELF. SO WITH GENOMIC PROFILING ASSAYS, PHYSICIANS ARE ABLE TO DO RISK PROGNOSTICATION, PREDICTIVE BENEFIT OF ADJUVANT CHEMOTHERAPIES, INFORMATION ON LIKELIHOOD OF CANCER THAT WOULD BE RAPIDLY GROWING AND METASTASIZING. ALSO HELPS TO IDENTIFY ACTIONABLE MUTATIONS. THIS IS A CLASSIC CLUSTER THAT WAS PRINTED IN PNAS BACK IN 2001, THAT’S WHERE IT ALL STARTED, THAT I REMEMBER ABLE TO LOOK AT TUMOR SAMPLES AND CLASSIFY THEM INTO SIX CATEGORIES THAT HAVE CLINICAL RELEVANCE. TO BASICALLY RELEVANCE TO PROGNOSIS AND TO THERAPIES. SO THE QUESTION IS, IS MOLECULAR PROFILING USEFUL? IN DETERMINING BREAST CANCER PROGNOSIS AND TREATMENT? ABSOLUTELY YES. BACK THEN WHEN THEY LOOK AT OVERALL SURVIVAL FOR SIX ESTABLISHED SUBTYPES BACK IN 2001, THEY SAW SIGNIFICANTLY DIFFERENT OUTCOMES FOR PATIENTS BELONGING TO THE VARIOUS GROUPS T. LUMINAL A SUBTYPE HAS BEST PROGNOSIS AND BASAL LIKE HAS WORST PROGNOSIS, THIS IS SHOWING MORE RECENT BUT SHOWING GENE EXPRESSION ARRAYS CATEGORIZE BREAST CANCER AND INFORM PHYSICIAN ABOUT PROGNOSIS AND THERAPEUTIC RESPONSE. THE LUMINAL AS ARE HORMONE RECEPTOR POSITIVE WHICH WE KNOW HAVE BETTER PROGNOSIS. THE TRIPLE NEGATIVE WE KNOW HAVE POORER PROGNOSIS AND THEY ARE ALSO P53 POSITIVE. P53 MUTATED SOD THEY FALL ALONG A CONTINUUM PRETTY WELL. DEFINITELY NEXT GEN SEQUENCING HAS MADE IT POSSIBLE TO SEQUENCE LARGE NUMBERS OF GENE, VERY HELPFUL TO THE ONCOLOGY FIELD. SO CLINICALLY ACTIONABLE MUTATIONS JUST TO DEFINE IT ARE THOSE THAT ARE PROGNOSTIC. EITHER PROGNOSTIC CORRELATED WITH BEHAVIOR OF THE TUMOR OR PREDICTIVE, CORRELATE WITH A RESPONSE TO THERAPEUTIC AGENT. SOME MUTATIONS ARE PATHOGENIC, DRIVER MUTATIONS BUT NOT SPECIFICALLY ACTIONABLE. AND I WANT TO MENTION WHAT’S IMPORTANT IS THAT TWO ASSAYS HAVE BEEN APPROVED BY THE FDA THAT ANALYZE TUMOR RNA TO PREDICT RECURRENCE AND SELECT PATIENTS FOR CHEMOTHERAPY. THE TWO FDA APPROVED ARE ONCO TYPE DX. THESE ARE IN USE IN THE CLINICAL REALM. SO THE (INDISCERNIBLE) ASSAY USES MICROARRAY TECHNOLOGY TO ANALYZE 70 GENES AND IT PLACES PATIENTS EITHER AT A LOW RISK CATEGORY OF DEVELOPING RECURRENCE OR HIGH RISK CATEGORY. SO ONE WHOSE ARE LOW RISK ACCORDING TO — HAVE 10% CHANCE OF RECURRENCE AT TEN YEARS, THOSE WHO ARE HIGH RISK ACCORDING TO THIS ASSAY WILL BE — HAVE 29% CHANCE OF RECURRENCE AT TIN YEARS. — AT TEN YEARS. ONLY ABLE TO BE USED IN PATIENTS WHO HAVE THE CRITERIA THAT ARE LISTED THERE. THIS IS APPROVED BACK IN 2007 AND IT’S COVERED BY INSURANCE. IT WAS VALIDATED BY A STUDY THAT SHOWED WHEN THEY USED THAT PARTICULAR ASSAY AND PATIENTS CAME OUT TO BE HIGH RISK AND THEY RECEIVED ONLY ENDOCRINE THERAPY, THEY HAD 76% DISTANT DISEASE FREE SURVIVAL BUT IF THEY WERE HIGH RISK ACCORDING TO THE (INDISCERNIBLE) AND THEY RECEIVE BOTH ENDOCRINE AND CHEMO, THEY HAD AN 88% DISTANT DISEASE FREE SURVIVAL. SO THE TEST WAS VALIDATED, THERE WAS 12% ABSOLUTE BENEFIT OF ADDING CHEMOTHERAPY TO THOSE PATIENTS DEEMED TO BE HIGH RISK. THIS IS ACTUALLY A TEST THAT’S MORE IN PRACTICE SPECIFICALLY BECAUSE IT’S NOT ONLY PROGNOSTIC BUT IT’S ALSO PREDICTIVE. IT ALSO PREDICTS THE LIKELIHOOD OF BENEFIT FROM CHEMO OR RADIATION TREATMENT SO THIS IS VERY IMPORTANT. PHYSICIANS USE IT BASICALLY TO PREVENT PATIENTS FROM GETTING TOXIC CHEMO IF THEY CAN AVOID IT SO A LITTLE BIT HOW IT WAS DEVELOPED. THEY USED AN RTPCR METHOD TO BASICALLY QUANTIFY GENE EXPRESSION AND IT WAS ORIGINALLY VALIDATED FOR PATIENTS WHO WERE ER POSITIVE HER-2 NEGATIVE NODE NEGATIVE WITH INVASIVE CANCER BUT RECENTLY ALSO EXTENNED TO THE 1 TO 2 NODE POSITIVE CATEGORY AS WELL. SO THEY START WITH 250 CANDIDATE GENES AND THEN FROM THAT THEY NARROWED IT DOWN TO THOSE GENES THAT HAVE SOME SORT OF PROGNOSTIC SIGNIFICANCE IN BREAST CANCER THEN FINALLY THEY NARROW DOWN TO 16 CANCER RELATED GENES THAT FELL INTO THREE CAT GUYS PROLIFERATION, ER RELATED INVASION RELATED, FIVE REFERENCE GENES SOME HOUSEKEEPING MISCELLANEOUS GENES, NAY DEVELOPED AN ALGORITHM BASED ON LEVELS OF EXPRESSION OF THESE GENES, TO RECURRENT SCORE FOR EACH SAMPLE GENE TESTED. THE PROGNOSTIC ABILITY OF THE ONCO TYPE WAS VALIDATED, THOSE PATIENTS WHO ACTUALLY, THEY USED A RETROSPECTIVE ANALYSIS FROM TISSUE FROM A PREVIOUS STUDY. THOSE PATIENTS CATEGORIZED AS HAVING A LOW RECURRENCE SCORE HAD LOWER RATE OF DISTANT DISEASE, THEY WERE LOWER RATE OF RECURRENCE AT TEN YEARS. IT FELL ON CONTINUUM. SO THE TEST WAS VALIDATED FOR PROGNOSTIC VALUE. THEY ALSO WANTED TO LOOK AT PREDICTIVE VALUE OF CHEMOTHERAPY BENEFIT SO PATIENTS WITH TUMORS WITH HIGH RECURRENCE SCORE HAVE LARGE ABSOLUTE BENEFIT OF CHEMOTHERAPY, SO PATIENTS HAVE RISK SCORE GREATER THAN 31 YOU CAN SEE THE GRAPH WITH AND WITHOUT CHEMOTHERAPY IS WELL SEPARATED. THOSE PATIENTS WITH TUMORS THAT HAVE LOW RECURRENT SCORE HAVE MINIMAL BENEFIT FROM CHEMOTHERAPY BUT THE BIG QUESTION IS WHAT ABOUT THE MIDDLE THAT HAD INTERMEDIATE RECURRENCE SCORE. WHAT DO WE DO WITH THOSE PATIENTS? DO WE GIVE CHEMOTHERAPY, DO WE NOT? THAT WAS NOT AND ANSWERED QUESTION AT THIS POINT. SO THE TAYLOR RX STUDY WAS DEVELOPED TO ANSWER THAT QUESTION, THIS IS A STUDY LED BY ECOG ACRON BUT IT WAS ACTUALLY LED BY THE NATIONAL CANCER INSTITUTE CTEP PROGRAM. ACTUALLY ONE OF MY MENTORS WAS FROM WHEN I WAS A FELLOW HERE, DR. JOANNE SJUSKI WAS VERY INVOLVED IN THIS TRIAL SINCE INCEPTION AND DESIGN AND CONCEPT. SO BASICALLY THEY ENROLLED 100 — 10,000 WOMEN WITH EARLY STAGE BREAST CANCER AND BASICALLY ONES WITH HIGH RISK CURRENT SCORE GOT CHEMO AND HORMONE THERAPY AS EXPECTED. THOSE WITH LOW RECURRENCE SCORE THEY JUST GOT HORMONE THERAPY BUT THE QUESTION IS WITH INTERMEDIATE GROUP WHAT TO DO, SO THAT WAS THE PRIMARY STUDY GROUP FOR THIS STUDY. THEY RANDOMIZED THEM TO EITHER HORMONE THERAPY ALONE OR TO CHEMO AND HORMONE THERAPY. JUST LAST YEAR THE RESULTS WERE PUBLISHED IN NEW ENGLAND JOURNAL OF MEDICINE, THIS WAS BIG NEWS FOR THE ONCOLOGY COMMUNITY. THIS IS A SURVIVAL CURVE, THIS IS A SURVIVAL CURVE HERE SO THERE WAS NO STATISTICALLY SIGNIFICANT DIFFERENCE IN INVASIVE DISEASE FREE SURVIVAL IN PATIENTS AMONG INTERMEDIATE GROUP WHETHER OR NOT THEY GOT CHEMOTHERAPY SO CHEMOTHERAPY DIDN’T BENEFIT THE GROUP. SO FOR THOSE WHO HAD A HIGH RECURRENT SCORE DESPITE THE FACT OF CHEMOTHERAPY THEY HAD MORE EVENTS AS YOU CAN SEE BY RED LINE, MORTALITY WAS HIGHERMENT BUT THOSE WITH LOW RECURRENT SCORE RECEIVING ONLY EARLY HORMONE THERAPY, THEY WERE — THE RISK OF DISTANT RECURRENCE WAS 1% FIVE YEARS SO MAKING HORMONE THERAPY ALONE AN EFFECTIVE CHOICE FOR THOSE PATIENTS. BUT THE BIG — THE BIG THANK WE LEARNED FROM THIS WAS THOSE THAT IN THE INTERMEDIATE CATEGORY THEY DO NOT DERIVE BENEFITS THIS IS SHOWING RECURRENCE SO IN STATISTICALLY SIGNIFICANT DIFFERENCE BETWEEN TREATMENT GROUPS AND THE PROBABLY OF DISTANT RECURRENCE IN NINE YEARS SO THIS IS FOR THOSE PATIENTS WHO HAVE RECURRENT SCORE IN THE INTERMEDIATE CATEGORY. THE BOTTOM LINE ONCO TYPE ASSAY WHICH WAS A LONG TIME IN THE MAKING, I WOULD SAY GOING BACK ALL THE WAY TO IT WILL — BACK IN 2001, THE ONCO TYPE ASSAY IDENTIFIES 70% OF WOMEN WITH NO CHEMOTHERAPY BENEFIT. AS WELL AS IDENTIFYING THOSE IN WHOM CHEMOTHERAPY MAYBE LIFE SAVING. SOFT THOSE IN THE — WITH THE RISK SCORE 0 TO 25 IF WE HAVE NOT USED THIS ASSAY 25% OF WOMEN WOULD HAVE BEEN OVERTREATED, CLINICAL FACTORS, 25% OVERTREATED WE WOULD HAVE GIVEN THEM TOXICITY OF CHEMO WHICH IS NOT A SMALL THING BECAUSE ALKYLATING AGENTS CAN CAUSE OTHER CANCERS. THEY CAN CAUSE MYLODISPLASTIC SYNDROMES, I HAVE SEEN IT IN THE CLINIC AND IT’S SAD YOU TREAT ONE CANCER AND PATIENT IS DOING WELL AND ALL OF A SUDDEN NOW THEY HAVE A LEUKEMIA. SO IT’S NOT A SMALL THING. THEN IN HIGH RISK CATEGORY, PATIENT WHOSE HAD RISK SCORE OF 26 TO 100, THE STUDIES SHOWED US THAT IF WE WENT TO CLINICAL FACTORS AND NOT MOLECULAR PROFILING WE WOULD HAVE UNDERTREATED 43% SO WE GAVE 43% MORE PATIENTS THE BENEFIT OF SOMETHING THAT COULD SAVE THEIR LIFE. SO THIS IS HUGE IN BREAST ONCOLOGY. SO WHAT ARE THE CLINICAL IMPLICATIONS OF MOLECULAR DIAGNOSTICS IN BREAST CANCER? TREATMENT BECOMING MORE PERSONALIZED FOR PATIENTS. WE KNOW THAT. THE NEXT GEN SEQUENCING IS INCREASINGLY BEING USED BUT WHAT WE DON’T KNOW IS IF ASSIGNING TREATMENT BASED ON SPECIFIC GENE MUTATIONS CAN PROVIDE CLINICAL BENEFIT AS FAR AS INCREASING OVERALL SURVIVAL. I GUESS IN ONCOLOGY WE LOOK AT EVERYTHING IN TERMS OF OVERALL SURVIVAL. THAT’S A QUESTION WE HAVE NOT ANSWERED. AND THIS IS AN AVENUE OF ONGOING INVESTIGATION AND THEY ARE LOOKING AT DIFFERENT — WE ARE LOOKING AT DIFFERENT COMBINATION S. IT WILL TAKE A WHILE TO GET THAT ANSWER. SO I’M GOING TO TALK BRIEFLY ABOUT ONE OR TWO TRIALS THAT WE HAVE IN THE CENTER FOR CANCER RESEARCH, WOMEN’S MALIGNANCY BRANCH VERY BRIEFLY. A LITTLE BACKGROUND, PROGRAM CELL LINE PDL 1 EMERGED AS AN IMPORTANT CANCER BIOMARER AND TARGET FOR IMMUNOTHERAPY, TARGETED BLOCKADE OF PDL 1 MAY HELP RESTORE OR UPREGULATE THE ABOUT TUMOR IMMUNE RESPONSE. PDL 1 IS EXPRESSED ON TUMOR CELLS AND TUMOR INFULL TRAITING IMMUNE CELLS WITHIN THE TUMOR MICROENVIRONMENT. WHEN PDL 1 BINDS TO PD 1 EXPRESS ON ACTIVATED T CELLS IT INDUCES T-CELL EXHAUSTION OR STATE OF INEFFECTIVE T-CELL ACTIVITY SO BASICALLY WANT TO BLOCK THAT INTERACTION. SO PDL 1 EXPRESSED ON ANTIGEN PRESENTING CELLS CAN ALSO INHIBIT T-CELL ACTIVITY BY BINDING TO CD8 0 SO YOU CAN INHIBIT THAT INTERACTION, THAT IS A WAY TO TARGET THE CANCER. DISRUPTING THE PDL 1 PATHWAY. THE BLOCKING OF PDL 1 BINDING TO PD 1 REVERSES EXHAUSTION AND STRENGTHENS ANTITUMOR ACTIVITY INHIBITING INTERACTION WITH CD8 0 AND PDL 1 TO PD 1 INTERACTIONS OF THE T-CELL AND TUMOR CELL SCORE, T-CELL CYTOTOXIC ACTIVITY AND AGENT DERVALUMAB IS A IMMUNOTHERAPY, IT BLOCKS PDL 1 BINDING TO PD 1 AND CD8 0 AND IT’S BEINGVATED ALONE AND — INVESTIGATED ALONE AND IN COMBINATION OF VARIETY OF KARENS. SO ONE APPROACH IN IMMUNOONCOLOGY IS THE COMBINATION BLOCKADE OF MULTIPLE IMMUNE CHECK POINTS WITH SMALL MOLECULE TARGETED THERAPIES. SO IN OUR BRANCH WE HAVE A TRIAL FOR TRIPLE NEGATIVE BREAST CANCER THAT COMBINES DERVALUMAB WITH A PARP INHIBITOR. SO THE PRE-CLINICAL JUSTIFICATION FOR THE COMBINATION IS THAT STUDIES HAVE SHOWN PARP INHIBITORS WILL UPREGULATE PDL 1 E PRESENTATION IN BREAST CANCER CELL LINES AND ANIMAL MEALEDS. THE COMBINATION OF PARP INHIBITORS AND ANTI-PDL 1 INHIBITORS INCREASES EFFICACY IN VIVO TO EITHER AGENT ALONE. SO WHAT IS — PARP INHIBITORS WHAT IS THE RATIONALE TO USE THOSE IN SOMATIC OR GERM LINE MUTATED BREAST CANCER? A NORMAL CELL THE RESPONSE TO NATURALLY OCCURRING OR INDUCED DNA DAMAGE CAN BE THROUGH EITHER BRACA PATHWAY, OR THE PARP ENZYMES. SO WHEN BRACA 1 OR 2 IS MUTATED CELL IS DEPENDENT ON OTHER MECHANISMS SUCH AS PAR AND IN THIS INSTANCE PARP INHIBITORS WILL CAUSE DOUBLE HIT CELL REPAIR MECHANISM, CELLS WILL ACCUMULATE DAMAGE AND DIE. SO PARP IS INVOLVED IN BASED EXSIGNATURES REPAIR, BRACA 1 IS DNA REPAIR AND BRACA 2 IS IN DOUBLE STRAND HOMOLOGOUS REPAIR. IF YOU KNOCK OUT ALL THESE PATHWAYS, THE CELL IS GOING TO HAVE TROUBLE. SO WE HAVE A TRIAL, BASICALLY WE HAVE TWO COHORTS. IN METASTATIC TRIPLE NEGATIVE BREAST CANCER PATIENTS THEY NEED TO BE MEASURABLE. THEY ARE TARGETED LESIONS WE HAVE TO SEE ON CT SCAN AND MEASURE SO WE CAN MEASURE RESPONSE. AND USE RESIST CRITERIA. WE HAVE TWO COHORTS ONE FOR BRACA WILD TYPE WHICH ARE OBVIOUSLY NOT MUTATED AND ONE MORE BRACA MUTATED PATIENTS. THEY RECEIVED 1500 MILLIGRAMS IV ON 28 DAY SCHEDULE AND ELAPRIB TAKEN DAILY, 300 MILLIGRAMS& TWICE A DAY. PRIMARY END POINT FOR OUR TRIAL IS RESPONSE RATE AND SECONDARY END POINT PROGRESSION FREE SURVIVAL OVERALL SURVIVAL AND TOXICITY. IT’S OPEN AND ACCRUING. SO ‘M GOING TO DO A BRIEFCASE REPORT OF A PATIENT ON THAT TRIAL. SO THE PATIENT IS A 37-YEAR-OLD FEMALE OF DOMINICAN ORIGIN WHO NOTED A LEFT BREAST MASS ON SELF-EXAM OCTOBER 2016. SUBSEQUENT ULTRASOUND SHOWED A 2.6 BY 1.6 BY 2.5-CENTIMETER IRREGULAR HYPERECOIC MASS. NO LYMPH NODES WERE NOTED. ULTRASOUND, INFILTRATING DUCTILE CARCINOMA, PATHOLOGICAL GRADE 3, NEGATIVE FOR ER PR HER 2 NEGATIVE BY FISH WHICH MAKES A TRIPLE NEGATIVE BREAST CANCER. GENETIC TESTING INDICATED THAT SHE HAD A GERM LINE BRACA ONE MUTATION. SHE WAS DIAGNOSED WITH CLINICAL STAGE 2 BREAST CANCER. SHE BEGAN NEOADJUVANT CHEMOTHERAPY, WHICH IS CHEMOTHERAPY BEFORE SURGERY, HAD THOSE DENSE SIGH TO BE SAN EVERY TWO WEEKS AND FOUR CYCLES OF THAT FOLLOWED BY CARBO PLATIN AND TACK SOLVE AND SHE HAD THAT EVERY THREE WEEKS FOR FOUR CYCLES. THEN UNDERWENT A BILATERAL MASTECTOMY AND LEFT SENTINEL NODE DISSECTION. SHE DID NOT HAVE A PATHOLOGICAL CR FROM THE NEOADJUVANT CHEMOTHERAPY. THE BEST PROGNOSIS IS WHEN PATIENTS HAVE CHEMOTHERAPY BEFORE SURGERY IF THERE IS NO TUMOR THAT IS VISIBLE SURGICAL PATHOLOGY THAT’S THE BEST PROGNOSIS. FOR PATIENTS WHO HAVE RESIDUAL TUMOR LEFT USUALLY THE PROGNOSIS IS NOT AS GOOD. NEOADJUVANT CHEMOTHERAPY IS ONE WAY TO ASSESS RESPONSE TO CHEMOTHERAPY. YOU CAN ACTUALLY SEE THE RESPONSE. SO THE SENTINEL LYMPH NODE WAS NEGATIVE, PATHOLOGICAL STAGE WAS 11B. THEN FOLLOW-UP CT SCAN IN SEPTEMBER OF 2018 THAT SHOWED PROGRESSION UNFORTUNATELY WITH A LARGE MASS IN HER LEFT SUB PECTORAL REGION, 5.5 BY 2.6-CENTIMETERS. A LEFT LYMPH NODE 1.5 BY 3.9 SENT METERS, THAT’S — CENTIMETERS IN THE MEDIASTINAL AREA. WHERE THE HEART AND LUNGS ARE. AND ENUMERABLE LUNG NO DUALS ON BOTH LUNGS. SHE ALSO HAD 1.6 BY 1.2-CENTIMETER LEFT NO DUAL AND BONE METASTASIS. IT SHOWED ALL LEAGUES WERE INTENSE HIGH METABOLIC RATE AND LIKELY CANCER. ULTRASOUND GUIDED BIOPSY OF LEFT SUB PECTORAL MASS WAS INDUSTRIAL RECURRENCE WITH BREAST CANCER, STILL TRIPLE NEGATIVE. IN OCTOBER 2018 SHE SCREENED PROTOCOL BEGINNING CYCLE 1 ON NOVEMBER 5, 2018, A CT SCAN PERFORMED AFTER TWO CYCLES ON JANUARY 7, 2019, IT SHOW AD DRAMATIC PARTIAL RESPONSE WITH 50% REDUCTION OF SIZE OF TARGETED LEAGUES IN LUNG AND LIVER. — LESIONS IN THE LUNG AND LIVER. AFTER TEN CYCLES SHE CONTINUES TO HAVE DRAMATIC RESPONSE WITH THE LAST CT IN SEPTEMBER SHOWING 82% DECREASE IN SIZE FROM BASELINE. SO THAT’S AMAZING. AND SO HERE IS JUST THIS IS ONE OF HER TARGET LESIONS, THIS IS FROM BASELINE NOVEMBER 2018 BEFORE SHE STARTED TREATMENT. THIS IS THE MASS IN HER SUB PECTORAL AREA, 4.4 BY 3.3-CENTIMETERS, MARKED OFF THERE WITH THE GREEN. AFTER TEN CYCLES IN SEPTEMBER JUST A COUPLE OF WEEKS AGO HER LAST CT SCAN THERE WAS NO MASS IN THE AXILLA AREA. NOTHING. AT BASELINE SHE HAD A LEFT LOBE LIVER MASS 3.7 BY 8.2-CENTIMETERS. AFTER TEN CYCLES YOU CAN HARDLY SEE RADIOLOGIST CALLED IT SOMETHING LIKE A MILLIMETER OR SOMETHING. YOU CAN HARDLY SEE ANYTHING. THIS IS HER LUNGS. AT BASELINE. ALL THE AREA IN THE MIDDLE, THAT’S THE AORTIC ARCH BUT YOU CAN SEE A LOT OF ADNOPATHY NEAR THE HEART AND IN BETWEEN THE TWO LUNGS. AND THOSE THINGS YOU CAN SEE, IT’S METASTATIC DISEASE BASICALLY. SO AFTER TEN CYCLES, IT’S RESOLVED. BEFORE I GO THERE, OUT OF ALL THE BREAST CANCER, THE TRIPLE NEGATIVE BREAST CANCERS ARE CONSIDERED MORE IMMUNOGENIC. IT SEEMS THAT THEY HAVE A HIGH INFILTRATION OF T-CELLS. IF YOU TAKE BIOPSY AND LOOK AT IT YOU WOULD SEE THAT MORE THAN LIKELY THEY HAVE MORE T-CELL INFILTRATION IN TUMOR MICROENVIRONMENT THAN OTHER BREAST CANCERS. SO THAT COULD BE ONE REASON THEY ARE MORE — AND ALSO BRACA MUTATE SOD THE PARP INHIBITOR WAS MORE EFFECTIVE IN HER. SO JUST BRIEFLY, ONE OR TWO SLIDES LEFT. CHECK POINT INHIBITORS ARE ALSO AN IMPORTANT AREA OF TARGETED THERAPY. CHECK POINT KINASE 1 AND 2 ARE CELL CYCLE REGULATORS, THEY HOLE THE CRAIG CYCLE AT CHECK POINTS TO ASSESS MISTAKES HAS BEEN MAKE REPAIR. CELLS IN THIS MECHANISM ACCUMULATE DAMAGE DNA AND EVENTUALLY DIE. THOSE TUMORS THAT HAVE REPAIRS IN DNA PROTEINS ARE MORSUS IS ACCEPTABLE TO THE EFFECTIVE CHECK POINT INHIBITORS LIKE IF THERE ARE PATIENT HAS BRACA MUTATION FOR EXAMPLE. SO THIS IS A TRIAL THAT WE HAVE THE COHORT FOR BREAST PATIENTS IS NOW CLOSED. WE HAVE YET TO ANALYZE ALL THE RESULTS BUT WE HAVE SEVERAL PATIENTS BREAST PATIENTS ON THIS TRIAL WITH GOOD RESPONSES AS WELL BUT FOR SAKE OF TIME I DID NOT PUT IT ON THIS ONE. SO THAT IS IT. THERE’S SOME SLIDES AFTER THAT BUT I WON’T TALK ABOUT THAT. THAT’S ALL. [APPLAUSE]>>ANY QUESTIONS? YOU HAVE SOMETHING GOING FOR THE TRIPLE NEGATIVE BREAST CANCER NOW.>>YES. SO TRIPLE NEGATIVE IS AN AREA THAT WE DEFINITELY NEED TO DO MORE RESEARCH ON BECAUSE THERE ARE MINIMAL CHOICES EXCEPT FOR CHEMOTHERAPY THERE’S NO — OBVIOUSLY WE CAN’T USE HORMONES, MINIMAL CHOICES IS SO A TARGETED THERAPY IMMUNOTHERAPIES ARE THE WAY TO GO. NEWSPAPER THERAPY SEEMS TO BE EFFECTIVE. IN THOSE THAT ARE BRACA MUTATED, PARP INHIBITORS AND SUCH ARE VERY AFFECTIVE SO IT’S VERY PROMISSION. PROMISING.>>WE’LL MOVE ON. OUR NEXT SPEAKER IS DEL RIVERO, SHE GOT HER MEDICAL DEGREE IN VERACRUZ, SHE DID RESIDENCY THERE THEN CAME TO THE STATES, SHE WORKED IN NEW YORK DOING MEDICAL RESIDENCY, SHE COMPLETED A FELLOW HIP IN ENDOCRINOLOGY, THEN SHE CAME TO NIH AND PARTICIPATING IN THE INTERINSTITUTE ENDOCRINOLOGY TRAINING PROGRAM. SHE HAS A LOT OF EXPERIENCE.>>I DID A LOT OF TRAINING.>>SO SHE’S DOING A SECOND FELLOWSHIP IN ONCOLOGY AT NCI. SHE’S BOARD CERTIFIED IN INTERNAL MEDICINE ENDOCRINOLOGY, DIABETES AND METABOLISM AND IS BOARD ELIGIBLE IN ONCOLOGY. SHE’S GOING TO TALK TODAY ABOUT PEDIATRIC CANCER, CANCER PRE-DISPOSITIONS SYNDROME.>>OKAY. THANK YOU SO MUCH. THANK YOU SO MUCH FOR THE INTRODUCTION. I DID A LOT OF TRAINING BEFORE THAT FOR YEARS AND YEARS OF SCHOOLING AND FELLOWSHIPS. SO I WANT TO ASK A QUESTION, HOW MANY OF YOU ARE POST-DOCTORAL FELLOWS? HOW MANY OF YOU ARE CLINICAL FELLOWS? OKAY. NOT THAT MANY CLINICAL FELLOWS. SO MY TALK WILL TALK ABOUT CANCER DISPOSITIONS SYNDROMES, SOME OF THE WORK WE DO AT THE NCI IN THE ONCOLOGY BRANCH, TO LET YOU KNOW MOST OF THE TALK IS CLINICAL BUT I’M HAPPY AND WELCOMING ANY IDEAS FROM THIS — THE FUTURE IS BRIGHT, WE NEED YOU GUYS TO ADVANCE THE SCIENCE IN ALL THESE DIFFERENT CHAMBERS. THE DIRECTOR CLINIC IN AREA OF EXPERTISE IS ENDOCRINE MALIGNANCIES, MAINLY NEOENDOCRINE TUMORS OF GI TRACK AND LUNG AS WELL AS ADRENAL TUMORS. SO WE’LL DISCUSS A LITTLE BIT ABOUT CHILDHOOD CANCER. CHILDHOOD CANCER IS RELATIVELY RARE. THERE ARE APPROXIMATELY 12,000 CASES ANNUALLY THAT AFFECTS CHILDREN IN AGE NEWBORN TO AGE 14 AND THEN ALSO REPORTED A 1,200 DEATHS ANNUALLY. POPULATION OF CANCER WE CAN SEE THAT THERE ARE MUCH LARGER NUMBER. AND IN POPULATION CANCER SECOND LEADING CAUSE OF DEATH AMONG CHILDREN. WE CAN SEE HERE THE MOST COMMON — FIRST COMMON CAUSE OF DEATH IN CHILDREN IS ACCIDENT FOLLOWED BY CANCER AND OTHER ANOMALIES HEART DISEASE, ET CETERA BUT JUST SHOW YOU INCIDENCE OF CANCER PEDIATRIC POPULATION AS WELL AS KNOWING MOST COMMON CAUSE OF DEATH. SO I’M GOING TO MOST COMMON CHILDHOOD CANCER PER YEAR WE CAN SEE HERE THE MOST COMMON IS LEUKEMIA, FOLLOWED BY BRAIN CANCER FOLLOWED BY NEUROBLASTOMA, ALSO RARE TUMOR AS WELL. THERE’S OTHER CANCERS HODGE KIN LYMPHOMA WAS TUMORS BONES AND HODGKIN’S DISEASE, ONE AREA OF DISEASE IS THIGH ROAD CANCER AND WE WILL TALK MORE ABOUT THAT AND WHAT WE ARE DOING AT NCI. SO ALL CANCERS THERE ARE DIFFERENT CANCER DEPENDENT ON AGE GROUP AS WELL. I WILL SHOW DURING THIS COURSE TALK ABOUT DIFFERENT TREATMENTS TO TREAT VARIOUS CANCER CHEMOTHERAPY SURGERY RADIATION STEM CELL TRANSPLANTATION AND NOW WITH NEW IMMUNOTHERAPY THAT’S SOMETHING THAT’S WING DISCUSS ABOUT THAT. AS WE CAN SEE MENTION A FEW OF THE IMMUNOTHERAPY TREATMENTS, ONE OF THE CAR T-CELLS LESS APPROVED FOR TREATMENT OF LEUKEMIA, SO WE HAVE MONOCLONAL ANTIBODIES IF YOU CAN GIVE AN EXAMPLE OF MONOCLONAL ANTIBODY IS? DO YOU HAVE AN EXAMPLE? THAT’S CORRECT. ONE OTHER ONE? ANYBODY? TRASTUZIMAB AS WELL. SO THAT’S ANOTHER ONE. SO THOSE ARE DIFFERENT — ANTIBODY IS BASICALLY SOMETHING WE CAN TART AND TREAT AS WELL. TAD TUESDAY HAS BEEN TARGETS HER 2, (INDISCERNIBLE) PDL 1 SO THOSE ARE TYPE 1 ANTIBODIES AS WELL AND TYPE OF BIOTHERAPY, CANCER VACCINES WE DEVELOP AT CANCER VACCINE TARGETED CEA AND THEN WE HAVE CAR T-CELL THERAPY AND OTHER IMMUNOTHERAPY. THIS IS JUST TO SHOW YOU THAT ADVANCES IN PEDIATRIC DRUG DEVELOPMENT AND TARGET ADULTS, CAN BE TREATED, HAVE BENEFIT OF CLINICAL BENEFIT AS WELL. CRISINTNIB IS APPROVED FOR SMALL CELL LUNG CANCER, ALSO APPROVED FOR T-CELL LEUKEMIA AS WELL AND TUMOR WE ALSO HAVE OTHER DRUGS — TARGETING CD 2 BLASTOMA. ONE THING THAT HAS CHANGE VIEW OF DIFFERENT TUMORS IN CHILDHOOD IS THE — TRK MUTATION TUMORS AND NOW WITH THIS DRUG THAT HAS BEEN APPROVED FOR ANY SOLID TUMORS THAT TARGET THESE MUTATIONS, THIS MUTATION IS FOUND IN SMALL CELL LUNG CANCER, ALSO IN THYROID CANCER AS WELL SO WE CAN SEE THERE’S SOMETHING WE CAN TARGET ADS WELL, ALSO SEE CLINICAL BENEFIT AS WELL. I WORK A LOT HERE AT NIH ABOUT CANCER AND DEVELOP OTHER TREATMENT OPTIONS AS WELL AS CANCER AND THERE’S TWO APPROVED AGENTS FOR TREATMENT OF ADVANCE UNDETECTABLE CANCER SUCH AS (INDISCERNIBLE) AS WELL. SO FORTH. SO SOMETHING TO KEEP IN MIND IS EARLIER YEARS 1992 TO 2005 ONLY 5% CLINICAL TRIALS ARE APPROVED FOR PEDIATRICS BUT NOW IN THE LAST SEVEN TO EIGHT YEARS APPROXIMATELY 16 OR ALMOST 17% PHASE 1 TRIAL IS NOW CLINICAL EFFICACY IN CHILDHOOD CANCER, THIS IS SOMETHING AT LEAST FROM PEOPLE THAT TREAT PEDIATRIC CANCER SOME THINGS WE ENCOUNTER IS THAT IN CLINICAL TRIALS THE AGE IS 18 OR ABOVE, WE DON’T INCLUDES KIDS AND WE WANT AT LEAST AT NCI TO INCLUDE 10, 12 YEARS OLD WE SEE CLINICAL BENEFIT IN YOUNGER PATIENTS BUT THAT’S SOMETHING WE TRY TO DISCUSS IN PEDIATRIC COHORT AND ALSO FDA TO TRY TO INCLUDE YOUNGER PATIENTS ON VARIOUS CLINICAL TRIALS, NCI BECAUSE OF CLINICAL BENEFIT. SOMETHING TO DISCUSS IS BURDEN OF CHILDHOOD CANCER NOT ONLY INCLUDES THE CHILD BUT ALSO THE PARENTS AND SIBLING SIBLINGS IF
SOMEBODY A CHILD IS DIAGNOSE WITH CANCER WE HAVE TO HAVE SUPPORT NOT ONLY FOR CHILD BUT ALSO FOR FAMILY AS WELL. NUMEROUS ISSUES ARISE DURING THE TREATMENT OF CHILDHOOD CANCER DEALING WITH THIS BURDEN AND ONE IS TO HAVE TO DEAL WITH IT, HOW TO TELL A CHILD THAT YOU HAVE A CANCER, AND SOME OF THEM MAY NOT BE A CURABLE CANCER SO HOW WE DISCUSS THAT WITH THE KIDS. HOWDIES CUSS DEALING WITH CHANGES IN KIDS GOING TO SCHOOLS AND WANTING TO LIVE NORMAL LIFE HOW DO WE DEAL WITH THAT AND EDUCATE THE FAMILY AS WELL FOR THAT DEALING WITH BLOOD DRAWS IMAGES STUDIES, THEY LOSE THEIR HAIR WHEN YOUNG AND SOMETHING THEY DEAL WITH SPECIALLY WITH CLASSMATES LOOK ALIKE ALL THAT CAUSES STRESS IN THE CHILD. BACK TO ALSO HAPPEN IN ADULT ADS WELL AND ALSO WHENEVER PARENTS FOCUS ON CHILD THAT HAVE THE NEED BUT WHAT HAPPENS WITH THE SIBLINGS, ALL OF THAT HAS STRUGGLE. EVEN PARENTAL RELATIONSHIP, SOMETHING TO ADDRESS AS WELL IN THE CHILDHOOD CANCER. SURVIVORSHIP. SOME OF THIS CHILD WERE DIAGNOSED WITH LEUKEMIA, NOW THAT WE HAVE — AFTER THAT DEALING WITH THE LATE EFFECTS OF THE TOXICITY PARTICULAR THERAPY, DEALING WITH CHILDHOOD CANCER SURVIVORS SO FORTH. ALSO SOMETHING TO UNDERSTAND HERE, THAT’S WHERE MY TALK GOES, ABOUT THIS SURVIVOR GUIDELINE AVAILABLE FOR THE CHILDREN ONCOLOGY GROUP, AS WELL HOW TO TREAT AND DEAL WITH THIS CANCER SYNDROMES, THAT’S WHAT I’M GOING TO TALK ABOUT, A GOOD PERCENTAGE OF CHILDHOOD CANCER IS ASSOCIATED WITH CANCER DISPOSITIONS SYNDROME, YOU MAY BE COME FAMILIAR WITH SOME OF THEM. WE WILL TALK MORE ABOUT THAT. WHAT IS CANCER — IT’S CAUSED BY GERM LINE MUTATION WHICH ALSO INCREASE RISK OF DEVELOPING CANCER. IT IS CAUSED BY ACTIVATING MUTATION OF TUMOR THAT PREVENTS TUMOR GROWTHS ONCO GENE OR ACTIVATING MUTATION OF GENE THAT PREVENTS TUMOR FROM FORMING AND TUMOR SUPPRESSER GENE. GERM LINE MUTATION IN TUMORS DON’T NECESSARILY HAVE MANIFESTATION TO AS WELL. WE HAVE SOMEBODY THAT HAVE MUTATION, GERM LINE MUTATION THOUGH THEY HAVE IT IN EVERY CELL IN THE BODY DIDN’T NECESSARILY DEVELOP TUMORS, WE WILL TALK MORE ABOUT THAT. SO WHY IT’S IMPORTANT? BECAUSE WE DISCUSS EARLIER UP TO 14% PEDIATRICS CANCER ARE ASSOCIATED WITH CANCER DISPOSITIONS SYNDROME. THERE ARE A LOT OF OVER 500 KNOWN CANCER DISPOSITIONS SYNDROMES, HOWEVER TALKING 500 CANCER PRE-DISPOSITIONSES THERE, WE WILL DISCUSS A FEW THAT MAY HAVE ALSO — AS WELL. AND THEN IT’S IMPORTANT TO IDENTIFY CANCER DISPOSITIONS TOO, WHY? THERE’S ACTIVE TREATMENT FOR ACTIVE CANCER ALLOW SURVEY LEARN FOR DIFFERENT TUMORS BECAUSE THESE CANCER HAVE DIFFERENT TUMOR TYPES AND ALSO IDENTIFY THE RISK OF FAMILY MEMBER RISK AND ALSO — AS WELL. WE TALK A LITTLE BIT ABOUT THAT. SO LET’S DISCUSS A CASE FIRST. WE HAVE A 14-YEAR-OLD MALE DIAGNOSED WITH LARGE NECK MASS, SUBSEQUENT ULTRASOUND SHOWED (INDISCERNIBLE) RIGHT FIBER MASS, FINE NEEDLE ASPIRATION OF THAT FIBER MASS SHOWED CELLS CONSISTENT WITH HYPERCROW MATTIC NUCLEI WITH SPINDLE CELL FEATURES CONSISTENT WITH MEDULLARY CANCER SO THIS IS A — WE CAN SEE SHAREHOLDER SOLID MASS HERE AND SPINDLE CELL PICTURES HERE AND THAT’S CONSISTENT WITH MEDULLARY CANCER. SO WHAT DO YOU WANT TO DO NEXT? DO YOU WANT TO (INAUDIBLE) SIX MONTHS? REFER TO SURGERY NOW, MEASURE (INAUDIBLE)? DO YOU WANT TO OBTAIN GENETIC COUNSELING OR MEASURE CYTOGLOBULIN LEVELS? WHAT DO YOU WANT TO DO? DO YOU HAVE AN ANSWER? WHAT DO YOU WANT TO DO? CANNOT HEAR YOU. THAT’S CORRECT ANSWER. WHY IS THAT? VERY GOOD. SO THIS IS — WE ARE THINKING OBJECT MEDULLARY CANCER, CANCER SYNDROME, ONE THING WE WANT TO LOOK AT SOMEBODY SO YOUNG IS ASSOCIATION WITH MEN 2A OR B. WE WILL TALK BRIEFLY ABOUT THAT. NOW U SEE THAT HIS CARCINOGEN WAS VERY HIGH, THAT’S NORMAL LEVEL, CA IS ALSO ELEVATED WHICH IS MARKER FOR MEDULLARY CANCER. SO I THINK — WHAT DO YOU WANT TO DO NEXT? YOU WANT TO SEND HIM TO SURGERY NOW? C. WHY IS THAT? WHY C? WHY YOU THINK THIS IS SO HIGH? DO YOU WANT MAKE SURE THE PATIENT DOESN’T HAVE ANY META SAYSIS ANY SIDE OF THE BODY SO MAKE SURE IN A PATIENT THAT HAVE GREATER THAN 500 YOU WANT TO DO ALSO IMAGE PROCEDURES TO RULE OUT METASTATIC DISEASE. THAT’S BASICALLY WHAT IS IN WITH MEDULLARY CANCER. SO WE CONTINUE THE CASE, THEY WENT LUMPECTOMY AND DISSECTION WAS RESECONDED. IN PATHOLOGY CONSISTENT WITH MEDULLARY CANCER TO CONFIRM DIAGNOSIS OF MEDULLARY CANCER THIS IS A PATHOGEN STAIN HOW IT LOOKS IN A PATIENT WITH MEDULLARY CANCER. SO SOMETHING TO UNDERSTAND ABOUT THYROID CANCER BUT IS DIFFERENT FROM OTHER CANCERS, IS THAT’S SPECIALLY FOR DIFFERENTIATED CANCER OTHERWISE CONFUSED BECAUSE WE ARE TALKING ABOUT CANCER BUT I WANT TO TELL YOU THE DIFFERENCE BETWEEN CANCER WHERE H IS PROGNOSTIC FACTOR, SO PATIENT YOUNGER THAN 55 YEARS OLD DO BETTER THAN PATIENT OLDER THAN 55. BUT MEDULLARY CANCER DOESN’T HAVE AN AGE DIFFERENTIATED FACTOR. THAT’S SOMETHING IN THE ENDOCRINE ONCOLOGY TO UNDERSTAND ABOUT THAT. THESE ARE THE DIFFERENT TYPES OF CANCERS, MOST COMMON IS WHAT WE CALL DIFFERENTIATED CANCER,& ACCOUNTS FOR ALMOST 88% OF WHOLE CANCERS. WE HAVE POP LAYER CANCER AND WE HAVE (INAUDIBLE) CANCER. WE KNOW AND UNDERSTAND THAT — CANCER HAVE DIFFERENT MUTATIONS THAT HAS BEEN ALSO ASSOCIATED WITH PROGNOSIS AS WELL, BRAF MUTATION. SO REMEMBER THAT I MENTION EARLIER ABOUT THIS ONE CRK SOMETHING WAS PAYING ATTENTION, WHAT IS THAT? HOW DO WE TREAT IT? YES, THAT’S RIGHT. SO THAT’S THE TRK INDICATIONS ALSO FOUND IN CANCER THAT MUTATION IS FOUND VERY TREATMENT THAT CAN BE QUITE EFFECTIVE AS WELL. THEN WE HAVE — THE OTHER TYPE OF MUTATIONS AS WELL AND ALSO AS WELL AS PROGNOSTIC. NOW WE DISCUSS MEDULLARY CANCER SO MOST OF THE MEDULLARY CANCER ARE SPOSH RAKEDDIC. HOWEVER, OF THIS SPORADIC LET ME JUST GO BACK A LITTLE BIT. SO YOU HAVE HUNDRED PERCENT HEADS LAYER CANCER. 75% ARE SPORADIC T. OUT OF SPORADIC HALF HAVE SOMATIC. 25% ARE GERM LINE. THAT HAS BEEN ASSOCIATED WITH CANCER DISPOSITIONS SYNDROMES EITHER IMMUNE — AND WE WILL TALK MORE ABOUT THAT. AND — CANCER VERY AGGRESSIVE, VERY BAD PROGNOSIS CANCER. THIS IS JUST TO SHOW YOU LADIES AND GENTLEMEN OF CANCERS WE CAN SEE OLDER, WE CAN SEE DIFFERENT AGE 0 TO 4 YEARS OLD, 5 TO 9. YOU CAN SEE DIFFERENTIATED CANCER IS OF COURSE LATER. AS A TEENAGER WHEREAS MEDULLARY CANCER WE CAN SEE HERE OF COURSE EARLIER ONE OF THE THINGS IS BECAUSE IT HAS 100% PENETRANT TO DISCUSS DISPOSITIONS SYNDROMES ASSOCIATED WITH MEDULLARY CANCER HAVE OTHER TUMOR MANIFESTATIONS AND WE WILL TALK MORE ABOUT THAT. GOING BACK TO HISTORY. PATERNAL GRANDMOTHER HAVE A HISTORY OF CANCER. (INDISCERNIBLE) GRANDFATHER WITH PROSTATE CANCER, MATERNAL GRANDMOTHER WITH CORONARY ARTERY DISEASE BLADDER KAREN AND THEN WE HAVE MATERNAL GRANDMOTHER SHE UNDERWENT SURGERY AND WHAT — I THINK — IF I REMEMBER WELL ON THIS PATIENT. SO PATIENTS PARENTS ARE HEALTHY NO HISTORY OF CANCER BUT HE HAS TWO BROTHERS 28 AND 25 YEARS OLD, ALSO HEALTHY. WHEN THEY DID THE GENETIC TESTING HE WAS TESTED POSITIVE FOR THE ONCO GENE 918 WHICH IS ASSOCIATED WITH MULTIPLE ENDOCRINE AFASCIA TYPE 2B. MOST ARE FOUND SPORADIC, 25% IN FAMILIES AS WELL. JUST TO MENTION HERE SOMEBODY THAT IS POSITIVE AS CANCER PRETTIES POSITION SYNDROME ALSO FOR CYTOMA. ANYBODY KNOW WHAT A B CROW MOW CYTOMA? IT’S TUMOR OF — THAT PRODUCES EPINEPHRINE. SO ANYTHING IS — WHENEVER YOU HAVE YOU FEEL ANXIOUS, YOU START TO SWEAT, YOUR HANDS SWEAT, THAT’S AN EFFECT OF YOUR ADRENALINE. AND YOUR BODY PRODUCES NORMAL CONDITION BECAUSE IT’S DEFENSE MECHANISM, HOWEVER, THERE IS A TUMOR IN ADRENAL GLAND, THOSE GET REAL EXACERBATED, BECAUSE OF THAT HAVE BLOOD PRESSURE IS VERY HIGH, YOU START SWEATING LIKE OUT OF THE BLUE WITHOUT ANY EXTRANEOUS PDD, THAT HAS SIGNIFICANT CARDIOVASCULAR EFFECT. THAT’S THE REASON IF YOU WANT TO SEND SOMEBODY TO SURGERY THE FIRST THING YOU NEED TO DO IS HAVE CROW MOW CYTOMA. BECAUSE OF THE SAKE OF TIME, THIS IS WHAT THE OLD SPECIFICATION WE WILL DISCUSS THE NEW SPECIFICATION, THE DIFFERENCE BETWEEN SPORADIC AND MEDULLARY CANCER, WE SAY THE MOST COMMON IS SPORADIC. WE FOUND 25 PIRS TO 30% ASSOCIATED WITH GERM LINE MUTATION ON THE ONCO GENE. SO WE HAVE MULTIPLE APLASIA TYPE 2A. WE HAVE A DIFFERENT CLINICAL ABOUT MEDULLARY CANCER, WE DISCUSSED ABOUT CHROMO CYTOMA. THERE’S ANOTHER PRESENTATION LESS COMMON WHICH IS PRIMARY HYPOTHYROIDISM. WHAT IS HYPERPARA? PARATHYROID GLANDS REGULATES IN YOUR BODY. SO YOUR CALCIUM IS HIGH. SO WE TALK ABOUT WHAT IS MEDULLARY CANCER, WE TALK ABOUT FIELDS AND WE TALK ABOUT PRIMARY HYPERPARA. SOFT 2B MEDULLARY CANCER IS MOST COMMON AND THEN OLDER CLINICAL MANIFESTATIONS OF THE CANCER. SO THIS IS JUST TO MENTION THERE IS A GENOTYPE PHENE TIME CORRELATION IN DEPENDENT ON WHAT WHEN THE DO GENETIC TESTING DEPENDING WHAT IS MUTATED, THEY CAN HAVE DIFFERENT CLINICAL PRESENTATION AS WELL. MOST COMMON PRESENTATION IS 634 MUTATION, THAT’S THE MOST COMMON ASSOCIATION WITH MEDULLARY AND PRIMARY HYPERPAA THYROIDISM, THEN IF WE HAVE — 2B THE MOST COMMON MUTATION IS 18 MUTATION. HOWEVER THIS MUTATION ASSOCIATED WITH MORE AGGRESSIVE FORM OF MEDULLARY CANCER. SO THESE ARE DIFFERENT CLINICAL MANIFESTATIONS OF 2B, THIS IS WHAT THEY HAVE LIKE THIS MUCOSAL NEUROMUSCULAR, YOU CAN SEE HERE THE MUCOSAL NEURO MAS. THEY CAN ALSO HAVE (INAUDIBLE) AS ONE OF THE THINGS CHARACTERISTIC ON MEN 2B. THIS IS SKIN CHANGES THE WHOLE AMYLOID OSIS. THAT’S COMMON AS WELL. ONE THING WE HAVE SEEN IN PATIENTS WITH MEN 2B IS WE HAVE THIS PULMONARY BLAST. THAT’S SOMETHING WE HAVE SEEN, WHY IS THIS HAPPENING? WE SEE COMMON PULMONARY BLIPS. BECAUSE OF THIS CLINICAL PRESENTATION 2B WITH PULMONARY BLOOD ONE RESEARCH WE HAVE DONE IS TO UNDERSTAND ABOUT THE PULMONARY FUNCTION OF PATIENTS WITH MEN 2B. HERE THIS IS UNPUBLISHED DATA, WE ARE BASICALLY STUDY ALL THE PATIENTS WITH MEN 2B, RARE TYPE OF CANCER AND 27B STUDY WE DID PATIENTS WHEREAS BASELINE AND WE HAVE CONTINUOUS FOLLOW-UP PULMONARY FUNCTION TEST IN PATIENTS THAT WERE EXPOSED TO THAT INHIBITOR, WE MENTIONED EARLIER THERE WAS TWO APPROVED AGENTS FOR MEDULLARY CANCER, (INAUDIBLE) EARLIER IN THE PRESENTATION. AND ALSO WE HAVE THE PATIENTS THAT HAVE THE NAIVE. WE CAN SEE THAT — WE SEE ALSO THE DEFICIENCY ON THE PULMONARY DEAF FUSION CAPACITY. DIFFUSION CAPACITY. IT DETERMINES HOW MUCH OXYGEN TRAVELS FROM YOUR — TO THE LUNGS TO THE BLOODSTREAM. IN PATIENTS WITH TK NAIVE WE CAN SEE HERE THEY ALSO HAVE A MILD TO MODERATE ABNORMALITIES ON DIFFUSION CAPACITY WITHOUT BEING ON TYROSINE KINASE AND WHY I MENTION THIS IS BECAUSE THE TYROSINE KINASE CAN POSE PULMONARY FIBROSIS, THIS IN THE LUNGS DECREASE TLCO SO THAT’S WHY IN PATIENTS THAT DID NOT RECEIVE TREATMENT FOR THE CANCER BECAUSE THERE IS ALSO — ON THE LCO SO WE DON’T KNOW WHY THIS IS HAPPENING BUT IT CAN ALSO TELL ME AS DOCTOR TREATING CANCER CHILDHOOD CANCER, WHAT KIND OF TREATMENT I NEED TO GIVE A PATIENT WITH ADVANCED CANCER. SO THIS IS JUST TO MENTION IN TERMS OF WHEN HAD BEEN IS DIAGNOSED WITH MEN 2A OR MEN 2B ONE OF THE THINGS WE RECOMMENDED IS A PATIENT HAS HIGH RISK TO DEVELOP MEN 2A AND B, ALL THOSE PATIENTS NEED TO HAVE — AT BIRTH, ONCE DIAGNOSED YOU NEEDECTOMY, MORE COMMON WHEN THEY HAVE 18 MUTATION ASSOCIATED WITH MEN 2B. IF PATIENT THAT HAS M,N 2A THEY HAVE THE MOST COMMON MUTATION. THEY SCREEN FOR MEDULLARY CANCER AT AGE 3 YEARS OLD BUT THE PROPHYLACTIC HAS TO BE DONE BEFORE AGE 5 AND AS WE DISCUSSED EARLIER — CYTOMA ALSO RECOGNIZE TO B SCREENED AS WELL. DEPENDENT ON MUTATION DIFFERENT, SCREENING TEASE TO BE DONE WITH STANDARDIZED GUIDELINES. THIS IS SHOW YOU HERE THAT IF THE PATIENT HAVE REPEATEDECTOMY THEY DO BETTER. SURVIVAL IN THOSE PATIENTS COMPARED TO THE ONES THAT ARE NOT RECEIVE THE –ECTOMY. HOWEVER, EVEN ON PATIENTS THAT HAVE METASTATIC DISEASE KNOWING THAT THIS PATIENT HAS INDULIN DISEASE, SHOULD DIE AFTER TEN YEARS OF AGE. BECAUSE OF THAT ONE THING WE ARE WORKING IS TO DEVELOP TREATMENT OPTIONS IN THE PEDIATRIC ONCOLOGY BRANCH WITH NATURAL HISTORY, MEN 2A TO DEVELOP MORE TREATMENT OPTIONS FOR THESE PATIENTS. THIS IS JUST PICTURE OF DIFFERENT MANAGEMENT OF MEDULLARY CANCER, ONE THING THAT THE DIFFERENCE — DISCUSSED EARLIER ABOUT BREAST CANCER THE MANAGEMENT IS DIFFERENT BREAST CANCER, MORE AGGRESSIVE IS NOT SOMETHING THAT WE HAVE THE TIME TO DO SURGERY HERE OR RADIATE HERE, SO MEDULLARY CANCER IS MORE I DID LENT DEFICIENT FOR LONGER TIME SO THAT’S WHY BECAUSE OF THAT WE CAN HAVE MORE TREATMENT RELATED TO DISEASE SPECIFIC SOMETHING THEY HAVE ONLY LIVER DISEASE FOR ABLATION EMBOLIZATION OF THE LIVER, IF THEY HAVE LUNG META DAYSIS THEY CAN BENEFIT FOR BONE MEDICINE TO PREVENT FRACTURES IN THESE PATIENTS WE DISCUSS EARLIER ABOUT SYSTEMIC THERAPY AND ALSO BECAUSE OF THE INDOLENT COURSE IS NOT GROWN TO ALSO RECOMMEND CLINICAL TRIAL FIRST LINE. HOWEVER FOR BREAST CANCER WE HAVE KNOW PATIENT WAS DIAGNOSED WITH SYSTEMIC CANCER IN CLINICAL TRIAL BECAUSE WE DON’T KNOW THE BENEFIT IN PATIENTS AND SURVIVAL IS IMPORTANT. THAT’S ONE THING TO MENTION THE DIFFERENCE IN EARLIER BREAST CANCER VERSUS MEDULLARY CANCER. THIS IS A PAPER THAT CAME FROM THE PEDIATRIC ONCOLOGY BRANCH, THIS IS JUST REPORTING THE OUTCOMES OF CHILDREN AND ADOLESCENTS WITH ADVANCED MEDULLARY CANCER. AND WE CAN SEE THAT THE RESPONSE, I DON’T KNOW IF — WE EXPLAIN ABOUT THE WEATHER PLOT, DO YOU KNOW ANYONE TELL ME WHAT THAT MEANS? BASICALLY HAPPY YOU ARE HERE SO WE CAN ALWAYS ADD MORE INFORMATION BUT BASICALLY EACH LINE IS A PATIENT HERE. BASICALLY THIS IS THE BEST RESPONSE RATE ON THE TUMOR. SO MINUS 20, THAT MEANS TUMORS DECREASE BY 20%, BY 40%, AND THIS IS BASICALLY THE BEST RESPONSE FOR THE TUMOR. SO ONE LINE IS PATIENT AND BEST úRESPONSE RATE TUMOR DECREASE IN SIZE. WE CAN SEE HERE WITH THIS THAT TUMORS DID RESPOND WELL BUT ONE THING THE RESPONSE WAS DURABLE SO WE CAN SEE HERE THE TIME OF RESPONSE AN THOSE HAVE DURABLE RESPONSES AS WELL. SO NOW WE (INDISCERNIBLE) WE WILL GO BACK BUT CHECKING THE TIME AND NOW LET’S GO WITH 2. THIS IS A 24-YEAR-OLD FEMALE PRESENTED TO THE NIH WITH A MEDICAL HISTORY OF HYPERTENSION FOR SEVEN YEARS A. . THIS IS SEVEN YEARS HYPERTENSION AND THE PRIMARY CARE POSITION ONLY PLAYS — BLOOD PRESSURE INCREASE FROM ONCE A DAY TO TWICE A DAY SO SHE HAS — CONSTIPATION 20 POINTS WEIGHT LOSS ONE YEAR, SIX CENTIMETER ABDOMINAL MASS, WE CAN SEE THIS IS A MASS THAT IS WAS FOUND ON — DO YOU KNOW ANYBODY DIFFERENCE BETWEEN PARACRINE GLIOMA? WE ASKED EARLIER ADRENAL GLANDS, GLANDS ON TOP OF KIDNEY PRODUCES THREE HORMONES, AL DOS ROANE, COURT SOL AND ADRENALINE. SO ANY TUMOR IN THE RENAL GLAND? B CHROMO CYTOMA, ANYTHING OUTSIDE THE ADRENAL GLAND IS PARAGLIOMA. BECAUSE YOUR NERVOUS SYSTEM IS EVERY IN YOUR BODY THE, CERTAIN NEURONS CONTROL HEART RATE AND BOW WE WOULD MOVEMENT BECAUSE OF THAT THEY CAN HAVE THIS — CAN BE ANYWHERE IN THE BODY, ANY TUMOR OUTSIDE IS CALLED — GLIOMA BUT IT’S HISTOLOGY JUST LOCATION. SO HISTORY H (INDISCERNIBLE) EARLIER, THESE ARE THE THE MEDICATIONS SHE HAD HISTORY OF CANCER, FATHER HEAVY SMOKER. WHO BROTHERS ONE WITH HYPERTENSION AND ONE WITH HASHIMOTO. NO HISTORY OF PARAGAIN GLIOMAS. SO WHAT NEXT? WHO WANTS TO DO PLASMA FREE POE OR EPINEPHRINESS? WHO WANTS TO DO A GALLEON SCAN? DO YOU WANT TO DO GENETIC TESTING? DO YOU WANT TO DO MEDICATION TO PREVENT EXCESS OF EPINEPHRINES OR A BETA BLOCKER? MEDICATION FOR BLOOD PRESSURE. WHAT DO YOU WANT TO DO? THIS IS A CROW MOW CYTOMA. SO YOU WANT TO TEST FOR METH — ADRENAL IS MEASURED IN THE PLASMA, YOU CAN MEASURE IN THE URINE. AND YOU CAN SEE HERE THAT — IS TUMOR MARKER FROM NEUROENDOCRINE TUMOR BUT YOU CAN SEE HOW NOREPINEPHRINE, SO HIGH, 14,000, THE — IS ONLY 112 TO 700 SO IMAGINE HAVING THIS AMOUNT OF NOR EVE NAVARIN IN YOUR BODY, YOUR BLOOD PRESSURE GOES HIGH, HEART RATE IS HIGH, EVERYTHING IS EXACERBATED. THAT’S ONE THING YOU NEED TO KEEP — WHEN PATIENT HAS CROW MOW CYTOMA, HAS VERY IMPORTANT EVALUATION FOR TO DIAGNOSE CROMO CYTOMA. SO WE DID A CT SCAN TO CONFIRM THE MASS. AND JUST TO LET YOU KNOW NEOENDOCRINE TUMORS WE DISCUSSED EARLIER CHARACTERIZED BY CAT TA ALCOHOL MEAN. THEY SORT, RELEASE AND ALSO — CATECHOL MEAN. WHEN YOU HAVE SOCIETIES OR YOUR HANDS SWEAT, SO FORTH. SO THERE’S IMPORTANT GENETIC FACTS WE NEED TO KNOW ABOUT GLIOMA, SO 35 TO 40% INHERITED SO GERM LINE MUTATION IS IMPORTANT, WE DISCUSSED EARLIER ABOUT CANCER PRE-DISPOSITIONS SYNDROMES. 15% OF THIS SOMATIC MUTATIONS. AND MORE THAN 20 GENES ASSOCIATED WITH CROMO CYTOMA, CONSIDERED THE MORE HER RED TEAR ENDOCRINE TUMORS. WE DISCUSSED EARLIER THE DIFFERENCE BETWEEN SIGH FOE MA AND PARAGLIOMA. SO YOU CAN SEE THIS IS ON TOP OF KIDNEYS SO ANY EXCESS HORMONE TO ISSUE IS CROMO CYTOMA, ANYTHING OUTSIDE OF ADRENAL GLAND YOU CAN SEE THE PARA>>AN GLIA CHANGE, IT CAN HAPPEN ANYWHERE IN THE HEAD AND NECK, YOU CAN SEE STRUCTURES IN THE NECK AREA, TUMOR WHEN THEY GROW HAVE SIGNIFICANT LOCAL INVASION. VERY DIFFICULT TO RESECT BECAUSE OF AREA. THEN WE HAVE A GLIOMA ANYWHERE FROM THE CHEST AND PELVIS. WE DISCUSSED EARLIER ONE THING THAT IS IMPORTANT TO KNOW IS BECAUSE OF THIS HORMONE THAT IS PRODUCED EXCESSIVELY, THAT CAN CAUSE HEART ATTACK OR MANY COMPLICATION, CARDIOVASCULAR COMPLICATIONS, THAT’S IMPORTANT AS WELL. THERE ARE DIFFERENT GENE ASSOCIATE WITH CROW MOW CYTOMA, PARAINGLY OWE MAS, MOST COMMON GENE BHL, MEN 2 WE HAVE SNATEING HYDROGENASE MUTATIONS, THAT’S CHANGED METABOLISM WITH OTHER CANCERS AS WELL. AND ONE SPECIFIC ONCOLOGY BRANCH HAS HISTORY N OF ONE WE WILL DISCUSS MORE ABOUT THAT. THERE’S FIVE MINOR SUSCEPTIBILITY CHAINS SO THESE ARE LESS COMMON MEASURE, THEY ARE MOST COMMON IN FIVE SUSCEPTIBILITY GENES. SO THE MOST — THE — ACCOUNTS FOR MOST 90% IN CROW MOW CYTOMA AND PARAGLIOMAS AND THE OTHER GENES LESS THAN 10%. ONE THING I ALWAYS SAY TO MY FELLOWS IS THAT WHEN WE WERE IN MEDICAL SCHOOL, OR LEARNING, BIOCHEMISTRY OR ANY TALKING ABOUT PARAGLIOMA, USED TO BE RULE OF TEN, 10% POPULATION, 10% TARGET BILATERAL BUT THAT IS NOT LONGER THE CASE BECAUSE NOW THERE’S BEEN ESPECIALLY THE LAST TEN YEARS MORE DISCOVERIES OF DIFFERENT TUMOR MUTATION ASSOCIATED WITH THE GLIOMAS. SO THE MUTATION GENE DISCOVERED HERE AT NIH GAIN OF FUNCTION MUTATION ASSOCIATED WITH PARACRINE GLIOMA AS WELL AS WHEN YOUR CONCENTRATION OF RBC IS HIGHER AND BECAUSE OF THAT HEMOGLOBIN IS HIGH. HRAS MUTATION IS 7% CROW MOW CYTOMA AS HRAS MUTATION. THAT IS ON KREBS CYCLE, ASSOCIATED WITH MULTIPLE GLIOMAS, ANOTHER ENZYME IN KREB CYCLE WITH PARAGLIOMASS THERE WAS A NEW GENE DISCOVERED ABOUT THE E PASS ONE MUTATION WITH ASSOCIATED WITH PARACRINE GLIOMA HEART DISEASE. WE TALK MULTIPLE ENDOCRINE NEOPLASIA TYPE 2, WE HAVE EARLIER WE DISCUSSED MEDULLARY CANCER MEN 2A AND THEN ALSO MEN 2B SO WE DISCUSS MEN 2A IS ASSOCIATED WITH MEDULLARY CANCER CYTOMA AS WELL AS HYPOPARATHYROIDISM, MEN 2B ALSO CANCER CYTOMA AS WELL AS DIFFERENT CHARACTERISTICS OF THE MEN 2B O MEN 2B. BHL IS ANOTHER CANCER POSITION SYNDROME ASSOCIATED WITH CYTOMA AND PARACRINE GLIOMA, UP TO 25% PATIENTS MAY DEVELOP GLIAL CYTOMA. OF THE PATIENTS THAT DEVELOP IT THEY HAVE BILATERAL DISEASE, VERY LARGE TUMOR VASCULAR TUMORS BUT ALSO VHL IS ASSOCIATED WITH OLDER TUMORS AS WELL. WE DISCUSS DISPOSITIONS SYNDROME EARLIER AND SCREENING OTHER TUMORS IS IMPORTANT WHEN PATIENTS ARE POSITIVE FOR THAT SPECIFIC MUTATION. FOR EXAMPLE VHL IS ASSOCIATED WITH BLASTOMAS, THAT’S MORE COMMON THAN CYTOMA IS RARE IN THOSEPATIENTS. PANCREATIC NEOENDOCRINE TUMORS, HERE THE NIH NCI WE HAVE A GROUP STUDYING CANCER WITH VHL AND SO FORTH. I WANTED TO TOUCH BRIEFLY ABOUT THE N OF ONE BECAUSE THAT’S A BIG PART OF ONCOLOGY BRANCH AND N OF 1 IN ONCOLOGY BRANCH, NF 1 IS A COMMON SINGLE GENE DISORDER MUTATION IN THE TUMOR SUPPRESSER GENE WE DISCUSSED EARLIER. SO THESE ARE THE FINDING OF N OF ONE, THEY HAVE A SPOT WE CAN SEE MERE, THEY LOOK LIKE LITTLE MODELS. THEY CAN ALSO HAVE (INAUDIBLE) YOU CAN SEE THIS IS A — ARISES FROM THE — THEY CAN GROWTH AND CAUSE A LOT OF DEFORMITY, ALREADY DIFFICULT TO MOVE ARMS. THAT IS SOMETHING WORTH MENTIONING HERE HAVE THIS CAN BE MALIGNANT AS WELL AND THEY CAN BE VERY AGGRESSIVE TOO. TUMOR ASSOCIATED WITH N OF ONE, ALSO HAVE LEUKEMIAS TOO. SO ALL THE MANIFESTATIONS CNS, PERIVASCULAR GASTRO INTESTINAL, ENDOCRINE, ONLY TWO TO FIVE PERCENT N OF ONE PRESENT SO IT’S VERY RARE. THIS IS WHAT A NEUROFIBROMA MAY LOOK LIKE. WE CAN HAVE MULTIPLE FIBROMAS THAT WE CAN SEE. THESE CAN BE VERY PAINFUL TOO. WE DISCUSS FIBROMAS INVOLVE MULTIPLE (INDISCERNIBLE) THOSE PROXIMAL NEUROFIBROMASS CONTAIN FIE BLOW BLASTS MASS CELLS, THEY CAN — FIBROBLASTS, IT SLOW GROW BUT THEY CAN GROW VERY LARGE. ONE THING IS BECAUSE — COMES FROM THE NERVE, VERY DIFFICULT TO RESECT THOSE TUMORS WITHOUT HAVING COMPLICATION OF THIS. THEY CAN ALSO HAVE THIS — WE CAN SEE HERE THIS IS THE LATEST, THE NEUROFIBROMAS IN THE FACE AND WE CAN SEE HOW THEY CAN DISFIGURE SOMEBODY, ALSO HAVE FUNCTIONAL IMPAIRMENT BECAUSE OF THIS. YOU CAN SEE THIS IS A WHOLE BODY MRI, THIS IS A MULTIPLE COMPLEX FORM NEUROFIBROMA AND YOU CAN SEE HOW IT LOOKS LIKE AND SEE AROUND THE EYE AREAS AS WELL. UNDERSTANDING THE PATHOLOGY OF THIS N OF ONE ONE OF THE THINGS THAT IS ASSOCIATED WITH PATHOGENESIS IS THAT MAP KINASE PATHWAY ON THESE PATIENTS AND THERE’S MET INHIBITOR. HERE THE NIH IS ESPECIALLY THE PEDIATRIC ONCOLOGY BRANCH CLINICAL STUDIES INVASIVE THEY HAVE THE LONGEST NATURAL HISTORY STUDY IN PATIENTS WITH N OF ONE AND WITH MEMBER INHIBITOR PATHOGENESIS HOW TUMORS MAY DEVELOP THEY SAW THAT THE USE MEK INHIBITOR TRIGGERS THE TUMOR, WE DISCUSS EARLIER ABOUT WE CAN SEE HOW SIGNIFICANT TUMOR HERE EVEN LOWER DOSE WE CAN SEE HOW TUMORS SWITCH IN SIZE. WE CAN SEE THE PICTURE OF FIBROMA HOW OVER TIME THEY WE CAN SEE CHANGES HOW TUMOR REDUCE IN SIZE. THIS IS PUBLISHED DATA, FIRST PUBLISHED IN NEW ENGLAND JOURNAL OF MEDICINE, PHASE 2 PUBLISHED WITH PI IN THE STUDY AND WE DISCUSS EARLIER ABOUT WHAT THE — IS AND WE CAN SEE THE SIGNIFICANT RESPONSE WE HAVE SEEN IN THESE PATIENTS HEMATO ANYBODY. P BEAUTIFUL RESPONSE AS WELL. AND SOMETHING EXCITING FROM THE PEDIATRIC ONCOLOGY BRANCH WHEN THEY DEVELOP. AND THEY HAVE CLINICAL BENEFIT OF HEMATONIB. THAT’S BIG PART OF THE PEDIATRIC ONCOLOGY BRANCH, NOW BACK EARLIER I MENTIONED SOME OF THE MUTATIONS ASSOCIATED WITH PARA IS THE SUCKSNATE HYDROGENOUS MUTATION. THIS IS A NICE MUTATION TO HELP US UNDERSTAND THE PATHOGENESIS HOW THESE TUMORS DEVELOP BUT — I DON’T KNOW IF ANYBODY SINCE IF YOU A SCIENTIST POST-DOCTORAL FELLOW IF THEY KNOW ABOUT KREB CYCLE BUT THIS IS THE CHAIN. SO THAT’S BASICALLY WHAT IS RESPONSIBLE FOR YOUR ATP PRODUCTION. YOUR ENERGY PRODUCTION. SO WE HAVE MUTATIONS WITHIN ANY SIGNS RESPONSIBLE FOR THIS PRODUCTION WHICH IS SUCKSNATE DEHYDROGENASE COMPLEX, THE SUCKNATE DEHYDROGENOUS COMPLEX AS A B C AND D BUT WHEN THERE’S MUTATION ON THIS GENE ASSOCIATED WITH THIS COMPLEX, WHAT HAPPEN IS THAT IN THE KREB CYCLE, SUCKSNATE BECOMES FUME RATE. SO THERE’S GOING TO BE ACCUMULATION OF SUCKNATE IN THE BODY MANY THE CELLS. AND THESE ACCUMULATION OF SUCCINATE IT IS GOING TO CAUSE LOO A HIGH POXIC STATE. SO NORMALLY THEY HAVE A CERTAIN AMOUNT OF OXYGEN IN CELL BUT WHEN YOU HAVE THESE MUTATION THERE’S GOING TO BE A HIGH POXIC STATE AND WHAT HAPPENS IS THAT THAT WILL STABILIZE THIS HYPOXIA INDUCIBLE FACTOR FOR CONDITIONS (INDISCERNIBLE) NEEDS TO BE DIFFERENTIATED. SO BUT WHEN NOT DEGRADE DESTABILIZE, THAT FACTOR BASICALLY CAUSE THE INCREASE IN MUTAGENESIS, CELL PERTURBATION, THAT’S THE PATHOGENESIS OF DEVELOPMENT OF THIS TUMOR ASSOCIATED WITH BMP BUT NOT ONLY THAT MUTATIONS IN SUCKSNATE HYDROGENASE HAVE BEEN SHOWN IN KIDNEY CANCER, PITUITARY TUMORS, SO FORTH SO OTHER MYOWE MAS AS TUMORS. I DON’T — FOR SAKE OF TIME NO DETAIL BUT BASICALLY HERE THERE IS NEVER SUB UNIT OF THIS SUCKSNATE DEHYDROGENASE COMPLEX NOW WE UNDERSTAND THAT THEY HAVE DIFFERENT CLINICAL MUTATIONS. GERM LINE AUTOSOMAL DOMINANT MUTATION. ANYBODY KNOW WHAT DOMINANT MUTATION? ANYBODY? BECAUSE WE HAVE AUTOSOMAL RECESSIVE. 50% CHANCE THAT — MUTATION. DEPENDING IF THERE IS — SUCKNATE DEHYDROGENASE IS PATERNAL TRANSMISSION MEANING MITOCHONDRIA IMPRINTED SO THAT MEANS IT’S STILL 50% CHANCE YOU HAVE MUTATION BUT IF FROM THE MOM OTHER THINGS CAN HAVE MUTATION, MUTATION COMES FROM THE DAD, IT’S STILL 50% CHANCE MUTATION BUT WILL DEVELOP TUMORS. SO THAT’S A DIFFERENCE BETWEEN GENETICS OF THIS DIFFERENT MUTATIONS. ONE THING WE ARE STUDYING HERE THE NIH SNATE CLINICAL MANIFESTATION SUCKSNATE DEHYDROGENASE B. OF ALL THE HYDROGENASE MUTATION THIS IS MORE AGGRESSIVE. YOU CAN SEE THE HIGH MALIGNANCY RISK BUT ALSO ASSOCIATED WITH KIDNEY CANCER AS WELL. SUCKSNATE HYDROGENASE D MUTATION PRIMARILY IN HEAD AND NECK AREA. NOT AS HIGH AS SUCKSNATE DEHYDROGENASE B MUTATION BUT ALSO WITH KIDNEY CANCER TOO. THIS IS ALSO A PAPER THAT CAME FROM OUR GROUP WHAT IS THE RISK DEVELOPING METASTATIC DISEASE IN SOMEONE WHO HAVE THIS MUTATION. THIS WAS A RETROSPECTIVE STUDY. BASICALLY THE STUDY THEY LOOK ALL PATIENTS WITH METASTATIC DISEASE OR HAVE CYTOMA AT TRIAL PRESENTATION IN PATIENTS YOUNGER THAN 20 YEARS OLD. WHAT THEY FOUND IS OF THE 32 PATIENTS, SO THEY FOUND MOST WERE 71% — 72% HAVE SUCKSNATE HYDROGENASE B. 10% HAVE SUCKNATE HYDROGENASE B, OTHERS HAVE DHL. AN IMPORTANT FACTOR FROM THIS ONE, PATIENTS THAT HAD SUCKSNATE HYDROGENASE MUTATION THEY DEVELOP METASTATIC DISEASE EARLIER COMPARED TO THE SDHD WHICH IS IMPORTANT TO KNOW BECAUSE BASED ON THAT, IF A PATIENT HAS SUCKNATE DEHYDROGENASE MUTATION YOU START EARLIER COMPARED TO PATIENTS TO PATIENTS WHO HAVE SUCCINATE DEHYDROGENASE B, THEY DEVELOP TUMORS EARLIER COMPARED TO SDHD OR C OR A. SO THIS IS AN IMPORTANT THING WE NEED TO KNOW ABOUT THIS. BACK TO PAGE 2, THIS PATIENT UNDERWENT EXPLORATORY — WE DISCUSS ABOUT THE (INDISCERNIBLE) SO THIS PATIENT NEEDS TO HAVE PROPER MEDICATION. WHENEVER THEY GOT SURGERY DONE WANT TO DECREASE CARDS OWE VASCULAR IMPLICATIONS OR MYOCARDIAL INFARCTION SOME PATHOLOGY WAS MIXED IN WITH PARACRINE GLIOMA AND THEN THEY HAVE MOST POST EMERGENCE, SOMETHING THIS PATIENT DIDN’T HAVE EARLIER, WHAT DO YOU WANT TO DO? YOU WANT TO DO MAYBE SCAN? WHAT IS THAT, THE GALLEON SCAN, A VERY — SCAN, A SCAN MORE SENSITIVE FOR DIAGNOSIS OF CYTOMA AND GLIOMAS. FOLLOW PATIENT UP OR DO GENETIC TESTING? IN THIS CASE GENETIC TESTING PATIENT HAD GENETIC TEST, SHE’S VERY YOUNG. SO EVERY CYTOMA, DO GENETIC TESTING. SO THAT IS WHY WE DISCUSS EARLIER ABOUT OTHER DRUGS ASSOCIATED WITH CYTOMAS AND PARACRINE GLIOMA. BASICALLY YOU ARE GOING TO TEST A GENE BASED ON THE CLINICAL PRESENTATION OF THE PATIENT. IF A PATIENT HAS — ALL DIFFERENT TUMORS, CNS BLASTOMA, KIDNEY CANCER, THEY HAVE ANY OF THOSE TUMORS THEN YOU CAN TEST FOR THAT. AND DEPENDING WHAT CLINICAL PRESENTATION THEY HAVE THEY MAY REFLECT WHAT CLINICAL TESTING YOU MAY WANT TO DO IN THOSE PATIENTS. SO FOR THE HEAD AND NECK, WE DISCUSS — SEHD ASSOCIATED WITH HEAD AND NECK GLIOMA, AND ANY TEST THAT PRESENT ALWAYS TEST FOR GHB. THAT’S VERY IMPORTANT. THERE IS NOT SYNDROMIC FORMULA PRESENTATION SO INFORMATION MAY BE NEEDED THAT’S WHEN YOUR BIOCHEMICAL PHENOTYPES TESTED FOR ALL THESE HORMONES MAYBE IMPORTANT. SO JUST FOR SAKE OF TIME THIS IS NOT SOMETHING THAT MOST LIKELY GOING TO USE IN YOUR WORK. BUT THAT’S SOMETHING IMPORTANT. AS WE CAN SEE THIS PATIENT UNDERWENT TESTING AND SHE WAS FOUND TO HAVE MUTATION POSITIVE. SO THIS PATIENTS IS IMPORTANT ALL THESE PATIENTS WHENEVER THEY FIND TO HAVE MUTATION THEY NEED A FULL BODY MRI. WHOLE BODY SCAN AS DISCUSSED EARLIER YOU CAN HAVE TUMORS ANY OTHER PLACE IN THEIR BODY BUT ALSO IMAGING STUDIES IS IMPORTANT AS WELL, FUNCTIONAL IMAGING STUDIES AND LIKE OTHER NEUROENDOCRINE TUMORS THAT IS WHERE A SCAN PLAY AS VERY IMPORTANT ROLE I WILL TELL YOU WHY. PATIENT — ANY TUMOR GREATER THAN FIVE CENTIMETER OR ANY PARACRINE GLIOMA REQUIRES FUNCTIONAL IMAGING STUDIES. THIS PATIENT HAD A CT SCAN THAT SHOWED THAT THE PATIENT HAD METASTATIC DISEASE ALREAD IN THE LIVER, VERY YOUNG TO HAVE METASTATIC DISEASE. SO WHAT DO YOU WANT TO DO? THAT’S WHEN YOUR GALLEON SCAN, WE DISCUSSED THE GALLEON SCAN. SO PATIENTS THAT HAVE DIAGNOSED WITH CROMO CYTOMA PARACRINE GLIOMA YOU CAN SEE THIS SCAN, YOU CAN SEE WELL IT’S NOT VERY GOOD, THE SCAN IS ONLY AVAILABLE AT THE NIH, NOT AVAILABLE OUTSIDE THE NIH. SO WE CAN SEE THAT WE SEE DIFFERENT TUMORS THIS IS THE — VERY USE, ANIMAL EXPERIMENT STUDIES YOU ALSO MAY DO DIFFERENT IMAGING MODALITIES AND FEG IS ONE. LOOK WHAT HAPPENED WHEN YOU DO GALLEON SCAN? YOU CAN SEE THE DIFFERENCE, DIFFERENT IMAGING MODALITIES. WHAT HAPPENS WITH THE PARACRINE GLIOMAS EXPRESS SO MUCH STATIN RECEPTORS IN THE CELL. AND BECAUSE THEY EXPRESS SO MUCH RECEPTORS IN THE CELLS YOU CAN SEE WHEN YOU INJECT ISOTOPE LIGHTS OUT LIKE A CHRISTMAS TREE SO THIS HAS CHANGED THE WAY WE DIAGNOSE THIS ENDOCRINE TUMORS, NEUROENDOCRINE TUMORS BUT ALSO FOR GLIOMAS AS WELL. SO THAT’S AN EXAMPLE OF THIS. SO THESE ARE KIND OF LIKE WHOLE GUIDELINE WHAT TO DO IMAGE STUDIES BUT I WILL SAY THAT’S OLD BECAUSE NOW WITH GALLEON SCAN WE HAVE THIS AVAILABLE AT THE NIH AND WE ARE DOING STUDIES USING THE SCAN FOR USE OF NEUROENDOCRINE TUMORS YOU CAN SEE THE DIFFERENCE IN THIS SO THAT’S AN IMPORTANT THING TO KNOW FOR THIS PATIENT AND DIAGNOSTIC EVALUATION AND WORK UP THAT THE PATIENT IS TO HAVE A GALLEON SCAN. DEPENDING ON GENETIC MUTATION, IMAGING STUDY NEEDS TO BE DONE BUT I WILL SAY IN TERMS OF ALL OF THEM I THINK GALLEON SCAN IS A GOOD SENSITIVE SCAN. THIS IS A STUDY THAT SHOWED THAT GALLEON SCAN IS BETTER THAN FG PET SCAN NOT ONLY FOR SUCCINATE DEHYDROGENASE MUTATION BUT ALSO PATIENTS WHOSE HAVE NO GERM LINE MUTATION AS WELL. RATES IDENTIFY AS WELL AS SENSITIVITY IS HIGHER COMPARED TO FET PET SCAN OR SOMETHING BETTER COMPARED TO OTHER FUNCTION IMAGING MODALITIES. THIS IS HOW WE — TREATMENT ALGORITHM FROM CYTOMA AS WELL AS MEDULLARY CANCER HAS UNDERLYNN COURSE NOT RAPIDLY GROWING TUMORS. SOME CAN, SUCCINATE DEHYDROGENASE B HAVE MORE AGGRESSIVE COURSE AND TUMOR GROWTH AS WELL. ONE THING WE NEVER ADDRESS AS ONCOLOGIST IN TUMORS, WHEN I SEE A PATIENT WITH CYTOMA AND PARAGLIOMA, I HAVE TO DETERMINE WHAT IS GROWTH RATE. IF SLOW GROWING WATCH IT IF IT’S MODERATE GROW MIDD IS APPROVED AGENT FROM FDA JUST APPROVED BEGINNING OF THIS YEAR, THAT COULD BE AN OPTION HOWEVER AS WE SAW EARLIER, THE DIFFERENT SCANS DOPA GALLEON SCAN NOT EVERY PATIENT IS POSITIVE ON THE MIT — SO BEFORE OPEN PATIENT MIT TREATMENT YOU NEED TO MAKE SURE YOU ARE DOING ANALYZE SCAN TO MAKE SURE IT’S POSITIVE. IF NEGATIVE YOU ARE NOT GOING TO OFFER MITT. CHEMOTHERAPY, FOR RAPIDLY PROGRESSING DISEASE. NIH WE HAVE FIRST PROSPECTIVE STUDY, JUST TO GO BACK A LITTLE BIT WHAT MOVE THERE IS. SO THE — I SHOW YOU EARLIER RECEPTOR TYPE 2, GALLEON SCANS ARE POSITIVE AT THE SAME TIME WE HAVE ACTIVE TREATMENT THAT TARGETS THOSE RECEPTORS IN THAT (INDISCERNIBLE). THAT’S SOMETHING WE HAVE AVAILABLE AT THE NIH. I’M FINISHED. THAT’S GOOD. WHAT IS PEDIATRIC CANCER SYNDROME? THERE ARE SPECIFIC RECOMMENDATIONS WE SAW EARLIER, SYNDROME ASSOCIATED WITH DIFFERENT TUMORS. AND THEN WE NEED TO MAKE RECOMMENDATIONS BASED ON RISK OF TUMOR DEVELOPMENT. THERE ARE VARIOUS GUIDELINES PRODUCED FOR RECOMMENDATIONS ABOUT — AND WE SAW IT EARLIER FOR THE MEDULLARY CANCER WE DISCUSS ABOUT WHEN TO DO SURGERY, WHEN WE DISCUSS ABOUT SUCCINATE DEHYDROGENASE MUTATION WE DISCUSS WHAT TO DO WITH SCREENING AND SURVEILLANCE. THEN WHY THIS IS IMPORTANT, WE ARE ABLE TO DIAGNOSE SOMEBODY WITH CANCER SYNDROMES, IF WE DECK EARLIER NODES WE CAN INTERVENE AS WELL. THEN WE CAN ALSO — BUT THERE ARE CHALLENGES AS WELL WE NEED TO UNDERSTAND. SOMETIMES THERE IS THIS — MEANING WHENEVER THESE PATIENTS EVERY TIME THEY HAVE — EVERY SIX MONTHS THEY HAVE TO HAVE — A LOT OF ANXIETY AS WELL AS SOMETHING THAT CAUSES SIGNIFICANT PSYCHOLOGICAL DISTRESS BUT ALSO THE SAME TIME FOR PEDIATRIC CANCER SYNDROME RARE, WE ALSO DEVELOP EVEN THOUGH WE DISCUSS TUMORS, WE STILL NEED TO DEVELOP THERAPIES THAT BETTER FOR CANCER AND ALSO DETERMINE BETTER DOLL TOOLS THAT DETECT CANCER EARLIER AS WELL. THANK YOU. [APPLAUSE] ANY QUESTIONS?>>FOR THE METASTATIC MEDULLARY THYROID CANCER YOU POINTED OUT THAT (INDISCERNIBLE) WAS EFFECTIVE. IN THE CHILDHOOD CANCER DO YOU NOTICE RESISTANCE?>>VERY GOOD QUESTION. LIKE ALL THE TYROSINE KINASE INHIBITORS WE HAVE SEEN MECHANISM OF RESISTANCE. YOU KNOW WHAT THAT MEANS? THAT MEANS THIS IS NERVOUS SYSTEM, ANYBODY?>>WE DISCUSSED THIS PREVIOUSLY.>>OKAY. SORRY. SO BASICALLY YES, SO YES, WE HAVE SEEN THAT A LOT AND WE TRY AND — WE ARE DOING PEDIATRIC ONCOLOGY BRANCH TRYING TO DO BIOPSY AS WELL AS TREATMENT, POST TREATMENT TO DETERMINE THAT EXACT MECHANISM SO WE KNOW WHAT IS HAPPENING THAT MECHANISM HAPPENS ALL ACROSS VARIOUS TYROSINE KINASE. I DIDN’T MENTION THIS BUT THERE IS A NEW DRUG VERY EFFECTIVE FOR MEDULLARY CANCER IS THE — TRIAL CRK TARGETED CRK, REMEMBER I MENTIONED EARLIER (INDISCERNIBLE) TRIAL WE DON’T HAVE A SPECIFIC NAME FOR IT. WE HAVE SEEN PATIENTS INVOLVED IN THOSE TRIALS THAT HAVE A SIGNIFICANT RESPONSE, IT GOES FROM 10,000 TO 15. IN A PERIOD OF A MONTH. CORRELATED ALSO WITH TUMOR RESPONSE. WE HAVEN’T ONE THING TO LOOK AT THOSE TRIALS AND WE WILL OPEN THAT TRIAL ALSO TO SEE TYROSINE KINASE FAMILY WITH SYSTEM MECHANISM. SO FAR IN THE PHASE 1 STUDY, PHASE 2 STUDY THEY HAVE NO — THERE’S SOMETHING THAT WILL BE IMPORTANT TO SEE ABOUT THAT. THAT’S CORRECT. THAT’S VERY GOOD. WE HAVE SEEN THAT WITH THE — AND EVEN THOSE PATIENTS IN THE STUDY, SOMETIMES THEY WERE — THEY ARE RESPONSE BY TIME OF PROGRESSION.>>THAT WILL DO IT. THANK YOU. [APPLAUSE]

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