The role of Tumor Biomarkers in Management of Cancer in Womencamlt.org/wp-content/uploads/2017/04/Womens-Oncology-Kaiser-.pdf · Breast Cancer Statistics Most commonly diagnosed cancer

Unrestricted © Siemens Healthcare Diagnostics Inc. 2015 All rights reserved.

The role of Tumor Biomarkersin Management of Cancer in WomenLinda C. Rogers, PhD, DABCC, FACBSenior Clinical Consultant

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Unrestricted © Siemens Healthcare Diagnostics Inc. 2015 All rights reserved.Author/DepartmentA91DX-150391-UC1-4A00

Objectives

1.List the current immunoassay tumor markers for breast, ovarian, andthyroid cancer and explain their utilization.

2.Understand the potential hematologic complications of cancer.

3. Describe the clinical utilization of HER-2/neu in metastatic breastcancer


Agenda

Overview of Cancer in Women

Thyroid Cancer

Ovarian Cancer

Breast Cancer


Tumor markers and cancer

. Tumor markers are most commonly used to:

• Guide treatment decisions

• Monitor treatment.

• Predict the chance of recovery.

• Predict or watch for recurrence.

Important considerations:

•Results and reference ranges may differ from

manufacturer to manufacturer

•Continued monitoring must be performed using the

same test and platform

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Answers for life.Unrestricted © Siemens Healthcare Diagnostics Inc. 2015 All rights reserved.

Thyroid Cancer

NewClaims

forThyroidAssays


Thyroid Cancer

Cancer…Inappropriate cell growth


Thyroid Cancer

The American Cancer Society’s most recent estimates for thyroidcancer in the United States for 2016 are:

•About 62,450 new cases of thyroid cancer (49,350 in women, and19,950 in men)

•About 1,980 deaths from thyroid cancer (1,070 women and 910 men)

Sources: Future Oncol. 2010 Nov;6(11):1771–79.Annals of Oncology. 2010;21(Supplement 5):v214-19.

x3


Thyroid Cancer Risk Factors

Sources: Future Oncol. 2010 Nov;6(11):1771-79.http://www.cancer.gov/cancertopics/pdq/treatment/thyroid/Patient/page1#Keypoint2http://my.clevelandclinic.org/disorders/thyroid_cancer/hic_thyroid_cancer.aspx

Age(25–65)

Familyhistory

Gender Exposure toradiation

Goiter Geneticfactors

Iodinedeficiency


Thyroid Cancer Symptoms

Sources: http://www.cancer.gov/cancertopics/pdq/treatment/thyroid/Patient/page1#Keypoint2http://my.clevelandclinic.org/disorders/thyroid_cancer/hic_thyroid_cancer.aspx

Swelling

Lump in the neck

Difficulty breathing

Difficulty swallowing

Hoarseness


Thyroid Cancer

FT3

T4

Thyroglobulin

Sodium

Urea

Albumin

Lactate dehydrogenase

CRP

Thrombocytes

Third-generation TSH

T3

CEA

Calcium

Creatinine

Alanine transaminase

Bilirubin

Hemoglobin

Leukocytes

FT4

Calcitonin

Anti-Tg

Potassium

Alkaline phosphatase

Chloride

CRP

Gamma-glutamyltransferase

Imaging

Modalities


Thyroid Cancer

Four types of cancer• Papillary (70-80%)• Follicular (10%)• Medullary (3%)

• Anaplastic (2%)

Thyroglobulin is synthesized/secreted by• Thyroid follicular cells• Differentiated thyroid cancer cells• Papillary• Follicular

Calcitonin is synthesized/secreted by• Thyroid cancer C-cells• Medullary thyroid cancer cells

Spencer CA, et al. Nat Clin Pract Endocrinol Metab. 2008 Apr;4(4):223-33.Krahn J, et al. Clin Biochem. 2009 Mar;42(4-5):416-9

Thyroid. The Merck Manual. 18th ed. 2006. p.1192-1206.


Differentiated Thyroid Cancer and Thyroglobulin

Differentiated thyroid cancer:

• Follicular

• Papillary

• Prognosis is excellent if found early

Treatment:

• Surgical

• Radioactive iodine ablation

Thyroglobulin utilization:

• Monitoring after treatment

• Presence indicative of relapse or inadequatetreatment

Thyroid. The Merck Manual. 18th ed. 2006. p.1192-1206.British Thyroid Association. http://www.british-thyroid-association.org/info-for-

patients/Docs/TFT_guideline_final_version_July_2006.pdf.American Thyroid Association (ATA) Guidelines Taskforce on Thyroid Nodules and Differentiated Thyroid Cancer,

Thyroid. 2009 Nov;19(11):1167-214.American Thyroid Association Guidelines Task Force. Thyroid. 2009 Jun;19(6):565-612


Well-Differentiated Thyroid Cancer

Tests for remaining thyroid tissue are particularly important formonitoring thyroid cancer patients for residual, metastasized, andrecurring thyroid tissue after the thyroid has been completelyremoved. Historically, the only procedure available to monitorresidual thyroid removal has been the total body scan

An appropriately sensitive Tg assay offers a powerful complementaryprocedure that may reduce reliance on the far more invasive totalbody scans

Anti-Tg antibodies interfere in the Tg assay, and Tg results maytherefore not be reported for serum samples that are positive forthese antibodies


Well-Differentiated Thyroid Cancer

Thyroglobulin (Tg) and Anti-TG (antibodies to Tg) tests are used:

Tg for monitoring thyroid cancer patients post thyroidectomy

Synthesized in thyroid gland as precursor to thyroid hormones T4, T3

Not detected in the absence of thyroid tissue

Increased in physical damage to the thyroid or in thyroid cancer

Used primarily as ‘tumor marker’ for detecting return of thyroid cancer

Anti-Tg screening of thyroglobulin samples for interference


Medullary Thyroid Cancer and Calcitonin

Calcitonin is the best marker for medullary thryoid cancer

Diagnosis

• Baseline measurement

• Positive correlation between levels and tumor mass

Monitoring therapy

• Regular measurement during follow-up post-operatively

• Elevated/rising levels should trigger further investigation

British Thyroid Association. http://www.british-thyroid-association.org/info-for-patients/Docs/TFT_guideline_final_version_July_2006.pdfAmerican Thyroid Association Guidelines Task Force. Thyroid. 2009 Jun;19(6):565-612


Thyroid Cancer Case Study

47-year-old presents with painless lump and fatigue.

TSH: normal; free T4: normal; total T4: normal; anti-TPO: present

Biopsy determines follicular cancer. Patient has surgery and takeslevothyroxine. Returns 2 months later.

TSH: normal; free T4: normal; thyroglobulin: undetectable;anti-thyroglobulin: undetectable

Diagnosis is euthyroid, with no biochemical evidence of tumor.


Ovarian Cancer

NewClaims

forThyroidAssays


Ovarian Cancer

Among women in the United States, ovarian cancer isthe eighth most common cancer and the fifth leading

cause of cancer death

accounts for only about 3% of all cancers in women

But causes more deaths than any other cancer of thefemale reproductive system


Ovarian Cancer

Sources: Breakaway: The global burden of cancer-challenges and opportunities.Economist Intelligence Unit Limited 2009.

http://www.ocrf.org/index.php?option=com_content&view=category&layout=blog&id=36&Itemid=293

Survivalrates

Detection

Consequences

120,000deaths

240,000diagnoses


Symptoms of Ovarian Cancer

Most common symptoms:• Bloating• Pelvic or abdominal pain• Trouble eating or feeling full quickly• Urinary symptoms such as urgency

Other Symptoms:• Fatigue• Upset stomach• Back pain• Pain during sex• Constipation• Menstrual changes• Abdominal swelling with weight loss


Ovarian Cancer Risk and Protective Factors

Source: Ovarian Cancer Prevention (PDQ®). National Cancer Institute atthe National Institutes of Health.www.cancer.gov/cancertopics/pdq/prevention/ovarian/Patient/

Age

Fertilitydrugs

Geneticfactors

(BRCA 1/2) HRT

Obesity

Familyhistory

Risk Factors Protective Factors

Oralcontraceptives

Tubal ligation/hysterectomy Oopho-

rectomy

Pregnancy/breastfeeding


How Is Ovarian Cancer Detected?

1.Signs and symptoms

2.Pelvic exam

3.Transvaginal/pelvic ultrasound

4.Blood tests

Source: National Cancer Institute. What You Need to KnowAbout™ Ovarian Cancer. Internet Edition. July 2006.

Diagnosis

Diagnosis


CA-125

•Also known as mucin 16 or MUC16

•90% of women with advanced ovarian cancer haveelevated levels of CA-125

•Monitoring CA-125 blood serum levels is also useful fordetermining how ovarian cancer is responding totreatment

• Preoperative value >65 U/mL suggests a poorprognosis

•Persistent elevations following chemotherapy indicate apoor prognosis.

•The half-life of CA-125 after chemotherapy correlateswith prognosis

Screening• Lack of sensitivity, particularly for detecting earlystages of ovarian cancer

• Lack of specificity

•May be elevated in the presence of any inflammatorycondition in the abdominal area, both cancerous andbenign


Caring for Women with Ovarian Cancer

CEA

Chloride

Sodium

Urea

Alkaline phosphatase

Albumin

Lactate dehydrogenase

Gamma-glutamyltransferase

Thrombocytes

CA 125

CRP

Potassium

Calcium

Creatinine

Alanine transaminase

Bilirubin

Hemoglobin

Leukocytes

Imaging

Modalities


Breast Cancer

NewClaims

forThyroidAssays


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Source: American Cancer Society

Breast Cancer Statistics

Most commonlydiagnosed cancer

in women

1 in 8women will

be diagnosedin the U.S.

1,000,000new global

cases diagnosedannually

Accountsfor 26% of all

cancers inwomen

5-yearsurvival

with earlydetection

is 90%

2nd leading cause of cancer deaths

in women

2.8 million survivors


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Breast Cancer Risk Factors

Source: Oncology Channel

RiskFactors

Age

Family History

Reproductive history


76%

20–24

Rate per 100,000300

150

100

50

025–29 30–34 35–39 40–44 45–49 50–54 55–59 60–64 65–69 70–74 75–79 80–84 85+

250

200

Age at Diagnosis

Breast Cancer Rates



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Source: http://www.cancer.gov/cancertopics/diagnosis-staging/staging

Elements of Staging Cancer

Location ofprimary tumor

Size

NumberLymph nodeinvolvement

Metastasis


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Sources: National Cancer Institute. What You Need to Know AboutBreast Cancer.™ Internet Edition. August 2012.American Cancer Society Current Guidelines: www.cancer.org.

How Is Breast Cancer Detected?

Diagnosis

Self exam

Clinical breast exam

Mammography

Ultrasound


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Breast Cancer:Five-year Survival Rates by Disease Stage

100%

90%

65%

40%

20%

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

in Situ Stage I Stage II Stage III Stage IV



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Partridge A, Winer E. N Engl J Med. 2009;361:2499-2501.

Screening Mammogram


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How Is Breast Cancer Treated?

Treatment

Surgery

Chemotherapy

Radiation

Targeted therapy

Hormone therapy

Depends on the type

stage

aggressiveness


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CA 15-3

BR

CEA

SerumHER-2/neu

Intended Use

Treatmentmonitoring and

follow-up

Assay Stage I Stage II Stage III Stage IV

Source: Siemens Instructions For Use.

Breast Cancer Tumor Markers


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CA 15-3 CA 27-29 BR-MAMUC-1 geneproduct

Breast Cancer Tumor Markers: Diagnostic Performance


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Serum HER-2/neu Clinical Utility inMetastatic Breast Cancer


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• Quantitative determination of HER-2/neu protein in human serum.

• HER-2/neu ECD is associated with higher tumor stage and moreaggressive form of breast cancer.

• Values obtained may be used in the follow-up and monitoring of patients withmetastatic breast cancer whose initial serum HER-2/neu level is greater than 15 ng/mL.

• Elevated level of HER-2/neu ECD correlates with worst prognosis.

• Should be used in conjunction with other clinical and diagnostic procedures.

Intended use:

Source: Siemens Instructions For Use.

Serum HER-2/neu


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Cases (thousands)

200

100

50

0

150

Breast Cancer

New Cases

Primary Breast CancerSource: American Cancer Society, 2007.

Impact of Breast Cancer

Deaths

Triple -

HER2 +

ER/PR +


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Impact of Breast Cancer

Cases (thousands)

200

100

50

0

150

Breast Cancer

New Cases

Deaths

Metastatic Breast Cancer

HER-2/neupositive

30–90%

Source: American Cancer Society, 2007.


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HER-2/neu Signaling Pathway: What Is the HER-2/neu Oncoprotein?

Growth factor

HER-2/neuprotein

Breastcancer cell

Breast cell


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Extracellular domain(ECD-p97-115Kd ligand-binding site)

Intracellular domain(Tyrosine kinase activity)

Transmembranedomain

Cytoplasm

Plasmamembrane

Sources: Sundaresan S, Penuel E, Sliwkowski MX. The biology of human epidermal growth factorreceptor 2. Curr Oncol Rep. 1999;1:16-22.Hynes NE, Stern DF. The biology of erbB-2/neu/HER-2 and its role in cancer. Biochim Biophys Acta.1994;1198:165-184.

Structure of HER-2/neu Receptor


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Specimen type

Technical complexity

Target

Interpretation

FDA-approvedclinical application

IHC FISH Immunoassay

Tissue

Moderate

p185

Subjective

Candidacy forHerceptin and Tykerb

Serum

Low

Extracellular domain, p105

Quantitative

Monitoring ofMBC patients

Tissue

DNA

High

Quantitative

Candidacy forHerceptin and Tykerb

Comparison of Lab Methods for HER-2/neu Testing

Source: Yeh I. Am J Clin Pathol. 2002;117(Suppl 1):S26-S35.


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Sundaresan S, et al. Curr Oncol Rep. 1999;1:16-22.Hynes NE, et al. Biochim Biophys Acta. 1994;1198:165-84.

Immunohistochemistry

Fluorescent in situ hybridization

Immunoassay

HER-2/neu Detection


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PMP

Anti-HER-2/neu MoAb(TA1)-AE: the light reagent

HER-2/neu(p105)

Solid phase = PMP + antifluorescein MoAb

Acridinium Ester

Fluorescein Paramagneticparticles

Reactiveisothiocyanate

form

+

HER-2/neu Serum Assay Measures the ECD by DoubleMAb-based Test (Sandwich)

Anti-HER-2/neu MoAb(NB-3)-FITC: FL conjugate reagent


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IHC images courtesy of M.J. Kornstein, MD, Medical College of Virginia.

Abnormal 2+ Abnormal 3+Normal 0 Normal 1+

Normal Normal Abnormal lowamplification

Abnormal highamplification

Tissue Determination of HER-2/neu Status


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Time

Concentration (ng/mL)

10

5

30

25

20

15

Disease Progression

Therapy Response

15 ng/mL

Serum HER-2/neu“Only FDA-cleared test to monitorchanges in HER-2/neu status for MBC”

HER-2/neu Monitoring


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>20%

Sources: Ali, et al. Serum HER-2/neu and relative resistance to TRASTUZUMAB-based therapy in patientswith metastatic breast cancer. Cancer. 2008;113:1294-1301Lipton, et al. Serial Serum HER2/neu Levels and Clinical Response Status for Study EGF20009-MetastaticBreast Cancer. ASCO Breast Cancer Meeting, San Francisco. September 7, 2007.

Serum HER-2/neu Monitoring

Time

Concentration (ng/mL)

10

5

30

25

20

15

Disease Progression

Therapy Response


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Patient tumor sample from primary diagnosis

HER-2 IHC/FISH NEGATIVE

>15 ng/mL

Retest primarytumor sample

Monitor serum HER-2 quarterly

If positive, report to oncologistfor Herceptin consideration

Serum HER-2 test

HER-2 IHC/FISH POSITIVE

Monitor serum HER-2

Report to oncologist forHerceptin consideration

Monitor serum HER-2 biannually

<15 ng/mL

If no primary tumor,biopsy metastatic lesion

~10–30% of breast cancer patients diagnosed HER-2–negative on the primary tumor have an elevatedserum HER-2 value (>15 ng/mL) in MBC.1,2

1. Carney WP. Personalized Medicine. 2005;2(4):317-24.

2. Yeh I. Am J Clin Pathol. 2002;117(Suppl1):S26-S3.

Typical Use of Serum HER-2 Testing Algorithm for Metastatic Breast CancerComplimentary to Tissue Testing


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Sandri, et al. Anticancer Res. 2004;24(2C):1261-66.

Months

Probability of survival

10 20 30 40 500

0.2

0.4

0.6

0.8

1.0

Serum HER-2/neu <15 µg/L

Serum HER-2/neu >15 µg/L

Treated with cyclophosamide and methotrexate

Baseline Serum HER-2/neu Levels and Overall Survival


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• HER-2/neu is overexpressed in a subset of breast cancer patients. (PBC 20–30% and 30–90% in MBC)

• Detects the circulating form of the HER-2/neu oncoprotein extracellular domain.

• May be used in the follow-up and monitoring of patients with metastatic breast cancer regardless of Txmodality.

• Is a biomarker for HER-2/neu-positive breast cancer.

• HER-2/neu-positive tumors are indicative of more aggressive forms of breast cancer.

• Is not intended to replace IHC or FISH.

• Is FDA-cleared for stage 4 metastatic breast cancer.

• Serum HER-2/neu greater than 20% decrease from baseline or <15 ng/mL indicates diseaseregression regardless of treatment modality

Summary of HER-2/neu


Hematologic Complications of Cancer

NewClaims

forThyroidAssays


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Hematology: The Case of an Increased Risk of Clotting in Cancer

Reduced survival

4- to 6-fold increased risk

Most common complication

Second-leading cause of death

Khorana AA, et al. J Clin Oncol. 2009 Oct 10;27(29):4919-26.Francis C. J Clin Oncol. 27:4874-80.


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Symptoms of DVT

Pain/tenderness

Redness/discoloration

Swelling

Nonspecific

Heit JA. Arterioscler Thromb Vasc Biol. 2008 Mar;28(3):370-2.Zhai ZG, et al. Chin Med J (Engl). 2010 Feb 20;123(4):485-90.McNamara I, et al. Acta Orthop. 2009 Dec;80(6):687-92.


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Symptoms of PE

Chestpain Coughing Shortness

of breath Anxiety

Fainting Hypotension HeartFailureWheezing

Diaphoresis Rapid Pulse

Chestpain

Shortnessof breath

Anxiety

Fainting Hypotension HeartfailureWheezing

Diaphoresis Rapid pulseSuddendeath

Geerts B, Demers C, Kearon C. The Thrombosis InterestGroup of Canada. Clinical Guide, Suspected PE. 2006.


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What Is D-Dimer?

D-dimer is a fibrin degradation product (FDP), a smallprotein fragment present in the blood after a blood clot isdegraded by fibrinolysis.

It is so named because it contains two cross-linked Dfragments of the fibrinogen protein.

D-dimer concentration may be used to helpdiagnose thrombosis.


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Questions?


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Linda C. Rogers, PhD, DABCC, FACBSenior Clinical ConsultantScientific & Clinical Affairs

Phone: (949)421-9101Email: [email protected]

Contact

Documents

The role of Tumor Biomarkers in Management of Cancer in Womencamlt.org/wp-content/uploads/2017/04/Womens-Oncology-Kaiser-.pdf · Breast Cancer Statistics Most commonly diagnosed cancer