Finding The Enemy Within Tumor Markers In Breast Cancer
Finding theenemy within tumor markers inbreast cancerContinuing Education SeminarVrajesh Pandya, Ph.D.Clinical Chemistry Fellow
Learning objectivesBriefly describe the types and characteristicsof tumor markers used in clinical setting123Provide an overview of breast cancerdiagnostic work-upElucidate the utility of breast cancer tumormarkers in the clinical chemistry laboratory
OutlinePart-1Basics ofbreastcancerPart-2Diagnosisof breastcancerPart-3Tumormarkers inbreastcancerPart-4Case study
Part-1Basics of Breast Cancer
What is cancer? CancerTumor Uncontrolled cell division Invasion of surrounding and distanttissues Oldest description: 3000 BC Egypt In 2021 1.9 million individualswill be diagnosed with cancerHealthytissueBlood vessel Men 970,250 cases Women 927,910 cases About 608,570 cancer-relateddeaths will occur in 20211.7-million-years-old fossil osteosarcomahttps://www.sciencemag.org; Novikov et al, British Journal of Cancer (2021)
What is breast cancer?Symptoms?FatDucts andlobulesStromaWhere does breast cancer mages/breast1 566 838.jpgCancer facts and figures, ACS (2021)
Part-2Breast Cancer Diagnosis
Breast cancer clearmorphology Higher grade more aggressive worse outcomesRakha et al, BCR (2010)
Breast cancer stagingTumor size, lymph node involvement, metastasisStage 0Stagec IStage IVStage IIStage III Higher stage extensive spread worse rade/
Breast cancer screening To identifyasymptomatic disease Tumor markers areNOT sensitive orspecific enough Mammography-basedscreening Benefit vs riskdebatable Unnecessary treatment Psychological stress Self-exam by reast-screening-pdq# 1
Part-3Tumor Markers in Breast Cancer
What are tumor markers? Tumor markers (TM) Biomarkers found in bodytissues, blood, or urine thatcan be elevated by thepresence of one or moretypes of cancer Proteins, enzymes, hormones,mRNA, CTC, ctDNA Produced by the tumor or by thebody in response to the tumorhttps://www.cusabio.com/c-20631.html
Types of tumor toringtherapyPreventativeIdentify subclinical diseaseCancer diagnosisEstimate survival outcomesTherapeutic response predictionTumor shrinkage or cancer recurrenceRisk prediction
Tumor markers performancecharacteristicsPerfect test In reality NoCancerLowTest resultQuestionable testDistribution CancerHighDistributionDistribution NoCancerLowCancerHighTest resultNoCancerCancerLowHighTest resultCourtesy: Dr. Lisa Johnson
SensitivityThe ability of a test tocorrectly identify thepopulation with disease(cancer)Distribution CancerLowTest resultFor tumor markers Good Sensitivity- Someone withcancer produces a high tumormarker result Poor Sensitivity- Someone withcancer produces a low/no tumormarker result False negative resultsHigh𝑆𝑁 𝑇𝑃/(𝑇𝑃 𝐹𝑁)Courtesy: Dr. Lisa Johnson
SpecificityDistribution The ability of a test tocorrectly exclude thepopulation without disease (nocancer)Test Result Good Specificity-Someonewithout cancer produces alow/no tumor marker result Poor Specificity- Someonewithout cancer produces a hightumor marker result Increased tumor marker forbenign conditions False positive resultsNoCancerLowFor tumor markersHigh𝑆𝑃 𝑇𝑁/(𝑇𝑁 𝐹𝑃)Courtesy: Dr. Lisa Johnson
SensitivityHow is the cutoff determined?1- SpecificityReceiver operator characteristic ttachment/34661288-1f8f-459e-b8b4-936efc49e9bc/fx1 lrg.jpg
Kaplan-Meier survival curvePercent surviving Evaluate biomarker relationship with patient outcomesMarker values cutoffMarker values cutoffTime -3-kaplan-meier-survival-analysis/
Breast cancer developmentEPEGFHormone/GF dependent breast cancerHormonereceptorsERPRHER2Normal sexual functionE estrogen; P progesterone; EGF epidermal growth factorImages prepared with biorender.com
Predictive biomarkersHormonereceptorsERPRHER280HR % cases604020Immunohistochemistry ofbiopsy specimens0HER2 TNBCImages prepared with biorender.com
Breast cancer therapiesTNBCHER2 ChemotherapyAnti-HER2 therapyCancer cell deathHR Anti-estrogen therapyImages prepared with biorender.com
Outcomes based on predictionHR /HER2 HR /HER2 HR /HER2 TNBCWang et al, Oncology Letters (2019)
Breast cancer related deathsare decliningBreast Biomarkers HER2 Improved therapies Herceptin Increased understanding of the diseaseCancer facts and figures, ACS (2021)
mRNA-based markersOverall survival (%)BIK LowBIK HighPp 0.05 BIK is an estrogen sensitive gene involved in apoptosisPandya et al, Oncotarget (2016)
Oncotype Dx andMammaPrintOncotype Dx RT-PCRMammaPrint MicroarrayKwa et al, Nature Reviews Clinical Oncology (2017)
DNA-based tumor markers BReast CAncer genes 1 and 2 Tumor suppressor genesBRCA2 Do not cause cancer Prevent cancer BRCA1About 1:400 individuals (0.25%) carryBRCA1/2 mutations Family history Common population: 12% women willdevelop breast cancer Women with BRCA1 mutations: 55 65% Women with BRCA2 mutations: 45% The Angelina Jolie effectChromosome 17Chromosome 13 Preventative double t-is-brca; ions-4173768
Serum-based tumor markers CA 15-3 and CA 27.29 Upregulated in breast cancer Shed by epithelial cells Stage II and III early detection ofrecurrence Stage IV monitoring therapy response Can be elevated in other malignancies ProteinbackboneGlycosylationCarcinoembryonic antigen (CEA) Produced by GI tissue during fetaldevelopment Very low levels in healthy adults Maybe elevated in breast, colon and lungcancers PEMCEAHER2/neu by ELISA Human Epidermal Growth FactorReceptor All serum-based markers are used tomonitor therapy response NOT for diagnosis poor specificityAgarwal et al, Front. Immuno. (2018); https://www.123rf.com/photo 78436891: Contemporary practice in clinical chemistry, 4 th Edition (2020)
Therapy responseTrends areimportant!Rising markers with 20-30% increase may suggest treatment failureTietz textbook of clinical chemistry and molecular diagnostics, 6th edition (2018)
Pre-analytical considerations Serum or plasma are usually of choice Recommended to store specimens at 4 C or 20 C Timing of specimen collection not too critical Avoid collection immediately after surgery false elevations Avoid testing for unfocused requests such as “tumormarker screen” or suspicion of “malignancy” from ED Lack of sensitivity and specificity for specific cancersshould be reiterated for consults on abnormal resultsTietz textbook of clinical chemistry and molecular diagnostics, 6th edition (2018)
Analytical interferences High-dose hook effect Antigen in vast excess Specimen carryover Heterophile antibodies Affect non-competitivesandwichimmunoassaysPreissner et al, JCEM (2003); Tietz textbook of clinical chemistry and molecular diagnostics, 6th edition (2018)
Summary of breast cancermanagementSuspicious lumpImaging studies1 tumor biopsyHistologyER, PR, HER2stainingTreatmentMonitortreatmentresponse
Part-4Case Study
Case study and questions 38-year-old female She felt a peanut-sized lump in her right breast andignored it thinking a swollen node due to a recent cold 3-months later the lump grew to the size of a walnut She had persistent headache and mood swings Visited her PCP who referred her to an oncologist
Case study and questions1. What is the oncologist likely to do? A.B.C.D.Perform surgery to remove the tumorOrder a biopsy to screen for breast cancerPrescribe chemotherapyPerform imaging studies to visualize tumors Imaging studies followed by biopsy analysis found aprimary tumor of 3.5 cm in diameter and a 1.2 cm lesionin the axillary lymph node Diagnosed with grade 2 stage II breast cancer Breast cancer subtype: Triple negative (TNBC)
Case study and questions2. What is the clinical team likely going to do next?A.Surgically remove the primary tumor and initiatechemotherapyB. Ask the patient to go home as this is not seriousC. Collect a pre-surgical serum specimen to determine thebaseline levels of CA 15-3 D. Both A and C Pre-surgical levels of CA 15-3 were 489 U/mL (RI: 0-31) 1 month later 35 U/L 2 months later 34 U/L 6 months later 15 U/L with no radiologicalabnormalities
Case study and questions3. What do these results likely mean?A. B.C.D. She never had cancerHer cancer is responding to therapy and is in remissionThe tumor is growing backShe will never have cancer recurrenceThe patient will be monitored over the next few monthsand put on surveillance to detect recurrent diseaseactivity
B. Order a biopsy to screen for breast cancer C. Prescribe chemotherapy D. Perform imaging studies to visualize tumors Imaging studies followed by biopsy analysis found a primary tumor of 3.5 cm in diameter and a 1.2 cm lesion in the axillary lymph node Diagnosed with grade 2 stage II breast cancer Breast cancer subtype: Triple .
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