2010 Breast Symposium: Plenary Lecture

8/8/2019 2010 Breast Symposium: Plenary Lecture

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2010 Breast Symposium: Plenary Lecture

Sophia K. Apple, M.D.Associate ProfessorDirector of Breast PathologyUCLA Medical Center

1. Comparison of breast cancers internationally2. AJCC 2010 TNM Stage

3. Neoadjuvant chemotherapy effect4. Whats new in breast cancer pathology?


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Breast cancer incidences

Projecting to 2010, the annual globalburden of new breast cancer cases will be1.5 million.

It is currently estimated that there will be atleast 170 190 new breast cancer casesannually for each 100,000 people at

Indonesia.


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Breast cancerincidence

Countries

# 1 Iceland : 39.4 per 100,000 females

# 2 Denmark : 30.4 per 100,000 females

# 3 Netherlands : 28.7 per 100,000 females

#4 Belgium : 28.7 per 100,000 females

# 5 New Zealand : 28 per 100,000 females

# 6 Ireland : 27.5 per 100,000 females

# 7 Hungary : 26.6 per 100,000 females

# 8 United Kingdom : 26 per 100,000 females

# 9 Germany : 23.5 per 100,000 females

# 10 Canada : 22.6 per 100,000 females
http://www.nationmaster.com/country/ic-iceland/hea-healthhttp://www.nationmaster.com/country/ic-iceland/hea-healthhttp://www.nationmaster.com/country/da-denmark/hea-healthhttp://www.nationmaster.com/country/nl-netherlands/hea-healthhttp://www.nationmaster.com/country/be-belgium/hea-healthhttp://www.nationmaster.com/country/nz-new-zealand/hea-healthhttp://www.nationmaster.com/country/ei-ireland/hea-healthhttp://www.nationmaster.com/country/hu-hungary/hea-healthhttp://www.nationmaster.com/country/uk-united-kingdom/hea-healthhttp://www.nationmaster.com/country/gm-germany/hea-healthhttp://www.nationmaster.com/country/ca-canada/hea-healthhttp://www.nationmaster.com/country/ca-canada/hea-healthhttp://www.nationmaster.com/country/gm-germany/hea-healthhttp://www.nationmaster.com/country/uk-united-kingdom/hea-healthhttp://www.nationmaster.com/country/hu-hungary/hea-healthhttp://www.nationmaster.com/country/ei-ireland/hea-healthhttp://www.nationmaster.com/country/nz-new-zealand/hea-healthhttp://www.nationmaster.com/country/be-belgium/hea-healthhttp://www.nationmaster.com/country/nl-netherlands/hea-healthhttp://www.nationmaster.com/country/da-denmark/hea-healthhttp://www.nationmaster.com/country/ic-iceland/hea-healthhttp://www.nationmaster.com/country/ic-iceland/hea-health


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# 11 Czech Republic : 22.2 per 100,000 females

# 12 Italy : 22 per 100,000 females

# 13 France : 21.7 per 100,000 females

# 14 Australia : 21.6 per 100,000 females

# 15 Austria : 21.5 per 100,000 females

# 16 Norway : 21.3 per 100,000 females

# 17 United States : 21.2 per 100,000 females

# 18 Luxembourg : 21 per 100,000 females

# 19 Spain : 19.5 per 100,000 females

# 20 Portugal : 19.3 per 100,000 females

Breast cancer incidence
http://www.nationmaster.com/country/ez-czech-republic/hea-healthhttp://www.nationmaster.com/country/it-italy/hea-healthhttp://www.nationmaster.com/country/fr-france/hea-healthhttp://www.nationmaster.com/country/as-australia/hea-healthhttp://www.nationmaster.com/country/au-austria/hea-healthhttp://www.nationmaster.com/country/no-norway/hea-healthhttp://www.nationmaster.com/country/us-united-states/hea-healthhttp://www.nationmaster.com/country/lu-luxembourg/hea-healthhttp://www.nationmaster.com/country/sp-spain/hea-healthhttp://www.nationmaster.com/country/po-portugal/hea-healthhttp://www.nationmaster.com/country/po-portugal/hea-healthhttp://www.nationmaster.com/country/sp-spain/hea-healthhttp://www.nationmaster.com/country/lu-luxembourg/hea-healthhttp://www.nationmaster.com/country/us-united-states/hea-healthhttp://www.nationmaster.com/country/no-norway/hea-healthhttp://www.nationmaster.com/country/au-austria/hea-healthhttp://www.nationmaster.com/country/as-australia/hea-healthhttp://www.nationmaster.com/country/fr-france/hea-healthhttp://www.nationmaster.com/country/it-italy/hea-healthhttp://www.nationmaster.com/country/ez-czech-republic/hea-health


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Breast cancer death rate # 1 Netherlands : 433 deaths per 100,000 people # 2 Italy : 418 deaths per 100,000 people # 3 Hungary : 411 deaths per 100,000 people # 4 Luxembourg : 409.7 deaths per 100,000 people # 5 Slovakia : 405.3 deaths per 100,000 people # 6 Ireland : 357.6 deaths per 100,000 people

# 7 Czech Republic : 335.4 deaths per 100,000 people # 8 New Zealand : 327.3 deaths per 100,000 people # 9 United States : 321.9 deaths per 100,000 people # 10 Australia : 298.9 deaths per 100,000 people # 11 Norway : 289.4 deaths per 100,000 people # 12 France : 286.1 deaths per 100,000 people # 13 Austria : 280 deaths per 100,000 people # 14 Sweden : 268.2 deaths per 100,000 people # 15 Finland : 255.4 deaths per 100,000 people # 16 United Kingdom : 253.5 deaths per 100,000 people Total : 5,350.7 deaths per 100,000 people
http://www.nationmaster.com/country/nl-netherlands/hea-healthhttp://www.nationmaster.com/country/it-italy/hea-healthhttp://www.nationmaster.com/country/hu-hungary/hea-healthhttp://www.nationmaster.com/country/lu-luxembourg/hea-healthhttp://www.nationmaster.com/country/lo-slovakia/hea-healthhttp://www.nationmaster.com/country/ei-ireland/hea-healthhttp://www.nationmaster.com/country/ez-czech-republic/hea-healthhttp://www.nationmaster.com/country/nz-new-zealand/hea-healthhttp://www.nationmaster.com/country/us-united-states/hea-healthhttp://www.nationmaster.com/country/as-australia/hea-healthhttp://www.nationmaster.com/country/no-norway/hea-healthhttp://www.nationmaster.com/country/fr-france/hea-healthhttp://www.nationmaster.com/country/au-austria/hea-healthhttp://www.nationmaster.com/country/sw-sweden/hea-healthhttp://www.nationmaster.com/country/fi-finland/hea-healthhttp://www.nationmaster.com/country/uk-united-kingdom/hea-healthhttp://www.nationmaster.com/country/uk-united-kingdom/hea-healthhttp://www.nationmaster.com/country/fi-finland/hea-healthhttp://www.nationmaster.com/country/sw-sweden/hea-healthhttp://www.nationmaster.com/country/au-austria/hea-healthhttp://www.nationmaster.com/country/fr-france/hea-healthhttp://www.nationmaster.com/country/no-norway/hea-healthhttp://www.nationmaster.com/country/as-australia/hea-healthhttp://www.nationmaster.com/country/us-united-states/hea-healthhttp://www.nationmaster.com/country/nz-new-zealand/hea-healthhttp://www.nationmaster.com/country/ez-czech-republic/hea-healthhttp://www.nationmaster.com/country/ei-ireland/hea-healthhttp://www.nationmaster.com/country/lo-slovakia/hea-healthhttp://www.nationmaster.com/country/lu-luxembourg/hea-healthhttp://www.nationmaster.com/country/hu-hungary/hea-healthhttp://www.nationmaster.com/country/it-italy/hea-healthhttp://www.nationmaster.com/country/nl-netherlands/hea-health


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Prostate 192,280 25%Lung & bronchus 116,090 15%Colon & rectum 75,590 10%Urinary bladder 52,810 7%Melanoma of the skin 39,080 5%Non-Hodgkin lymphoma 35,990 5%Kidney & renal pelvis 35,430 5%Leukemia 25,630 3%Oral cavity & pharynx 25,240 3%Pancreas 21,050 3%All Sites 766,130 100%

Estimated New Cases of Cancer in male

Lung & bronchus 88,900 30%Prostate 27,360 9%Colon & rectum 25,240 9%Pancreas 18,030 6%Leukemia 12,590 4%

Liver & intrahepatic bile duct 12,090 4%Esophagus 11,490 4%Urinary bladder 10,180 3%Non-Hodgkin lymphoma 9,830 3%Kidney & renal pelvis 8,160 3%All Sites 292,540 100%

Cancer Deaths in male

American Cancer Society Data


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Breast 192,370 27%Lung & bronchus 103,350 14%Colon & rectum 71,380 10%Uterine corpus 42,160 6%Non-Hodgkin lymphoma 29,990 4%Melanoma of the skin 29,640 4%Thyroid 27,200 4%Kidney & renal pelvis 22,330 3%Ovary 21,550 3%

Pancreas 21,420 3%All Sites 713,220 100%

Lung & bronchus 70,490 26%Breast 40,170 15%Colon & rectum 24,680 9%Pancreas 17,210 6%Ovary 14,600 5%Non-Hodgkin lymphoma 9,670 4%Leukemia 9,280 3%Uterine Corpus 7,780 3%Liver & intrahepatic bile duct 6,070 2%

Brain & other nervous system 5,590 2%All Sites 269,800 100%

Estimated New Cases of Cancer in female Cancer Deaths in female

American Cancer Society Data


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Top 5 common primary cancers

1991No

Site

1 Cervix

2 Breast

3 Lymph node

4 Skin

5 Nasopharynx

2002-2006No

Site

1. Prostate

2. Breast

3 Lung

4 Colon &rectum

5 Uterus

Indonesia U.S.


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1. Comparison of breast cancers internationally

2. AJCC 2010 TNM Stage3. Neoadjuvant chemotherapy effect4. Whats new in breast cancer pathology?


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History of AJCC

AJCC (American Joint Committee onCancer Staging and End-ResultsReporting) began in 1959.

In 50 years, we have 7 th edition 6 th Edition: recommendation of N stage

divided into 3 categories based on the

number of axillary LN 7 th Edition: ER, PR and Her-2/neu status isnow considered standard of care


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AJCC 7 th Edition 2010

pT stage, the microscopic measurement isthe most accurate and preferred methodwith a small invasive cancer that can beentirely submitted in one paraffin block

The gross measurement is the mostaccurate and preferred method with largerinvasive cancer (possible with most IDC)


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Post-treatment after neoadjuvantchemotherapy staging is added (ypTNM)

ypT defined as the largest contiguousfocus on invasive cancer

ypN: nodal mets no greater than 0.2 mmclassified as ypN0 (i+) but this is notconsidered to achieve complete pathologicresponse (pCR)


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Tis (DCIS) Tis (LCIS)

Tis (Pagets): Pagets disease with nounderlying noninvasive (DCIS or LCIS) Recommendation to provide in situ size

estimation (for SLN management)


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Inflammatory carcinoma is restricted toclinical findings of typical skin changes(involving >1/3 of breast skin)-No histologic changes (dermal LVI) isneeded-Dermal LVI only without clinical findings isnot sufficient for a diagnosis ofinflammatory carcinoma


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pN0 (i+): isolated tumor cells in clusters 6 sentinel lymph nodes areidentified, the modifier (sn) should beomitted.


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New M (i+): defined by presence of eitherdisseminated tumor cells detected in bonemarrow or circulating tumor cells foundincidentally in other tissue (such asovaries removed prophylactic) if notexceeding 0.2 mm


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70-gene multigene expression assays(mammaprint) are now cleared by FDA forwomen less than 61 years of age with

stage I or II, Node negative breast cancer 21-genes by RT-PCR recurrence score

assay (oncotype) is now recommended(can be used) by ASCO (AmericanSociety of Clinical Oncology) for womenwith ER positive and node negative


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7 th Edition: ER, PR and Her-2/neu status isstandard of care

Luminal

Her-2/neu + Basal-like CA

ER


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Anatomic stage/Prognostic groups

Stage 0 Tis N0 M0 Stage IA T1 N0 M0 Stage IB T0/T1 N1mi M0

Stage IIA T0/T1 N1 M0 or T2 N0 M0 Stage IIB T2 N1 M0 or T3 N0 M0 Stage IIIA T0/T1/T2 N2 M0 or T3 N1/N2 M0 Stage IIIB T4 N0/N1/N2 M0

Stage IIIC any T, N3 M0 Stage IV any T, any N, M1


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Normal Duct DuctalHyperplasia

AtypicalDuctal

Hyperplasia

DuctalCarcinoma

In Situ

InvasiveDuctal

Carcinoma

No Treatment Detect and

Treat

Breast tumor progression model

Ductal hyperplasia :


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Normal cell :Predisposing genetic risk factors:BRCA-1 17q21BRCA-2 13q14TP53 17p13PTEN 10q23

Ductal hyperplasia :Overstimulation of cellcycle suppression ofapoptosis :ERPRGrowth factors:Her-2/neu 17q12

C-Myc 8q24Cyclin D 11q13AIB-1 20q12CDKN2(p16) 9q21RB-1 13q14TP53 17p13E-cadherin 16q22-23Immortalization of cells byexpression of Telomerase

DCIS :Mutations in growth factors, sex steroidpathwaysMutations in cell death pathways

Overall chromosomal instabilityInvasive carcinoma:Further phenotypic alterations incell cyclecell deathgrowth factor

Metastatic carcinoma:Angiogenesis metastatic spreadMutations in pathways in invasion

PAI-1Cognate inhibitor of urokinaseHAI-1

Cognate inhibitor of matriptaseDefects in mismatch repair of DNA


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Low Grade

ADH Grade 1 DCIS

Grade 1 IDCTubular/cribriform caTubulo-lobular caClassic ILC

Normal

High GradeGrade 3 DCIS (luminal)

Grade 3 DCIS (Her-2)

Grade 3 DCIS (basal)

Grade 3 IDC (luminal)

Grade 3 IDC (Her-2)

Grade 3 IDC (Basal)

Grade 2 DCIS (luminal) Grade 2 IDC (luminal)

CCLALH/LCIS16q- (85%)

1q+16p+

8q+

1q+17q+20q+13q-16q- (30%)

E-cad-


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History of Breast Cancer Treatment

Adjuvant Chemotherapy

Lumpectomy Adjuvant Chemotherapy

Radical mastectomy ALN

ALN

NeoadjuvantChemotherapy

Lumpectomy

Modified radicalMastectomy

SLNHormonaladjuvanttherapy

+

+

+/-bx


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Buchholz 2003

Post-NACT size


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Number of 1 cm levels involved = span of residual tumor

Mastectomy


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Complete pathologic respond: cPR


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Complete pathologic respond


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Invasive lobular carcinoma after neoadjuvant chemotherapy


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Post-NACTEffect on LNOf IDC


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Intrinsic classification


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Ref: Perou CM et al. Molecular portraits of human breast tumors. Nature 2000:406 (6797); 747-52

Breast tumors originate from different mammary epithelial cell types

cDNA microarrays

Her-2/neuPositive tumors

Her-2/neuNegative tumors

Luminal AER/PR+ N1

Luminal BER+ PR-

Basal-likeTriple -


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N/AN/A

Site No. PopulationNSABP B-20Study,Pittsburgh,PA

233 Node ER +Tam (100%)

RushPresbyterian,Chicago, IL

78 > 10positivenodes

ER +/-

Tam (54%)Chemo (80%)

ProvidenceSt. JosephsHospital,

Burbank, CA

136 Node +/- ER +/-Tam (41%)

Chemo (39%)

GHI assay tested 250 candidate genes in 447 patients

21 Genesand Algorithm forRecurrenceScore (RS)

Three Breast Cancer Studies Used to Select 16 Cancer


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Three Breast Cancer Studies Used to Select 16 Cancerand 5 Reference Genes: 21 total genes: weighted most

for ER, Her2 and Proliferation

PROLIFERATIONKi-67

STK15Survivin

Cyclin B1MYBL2

ESTROGENER

PGRBcl2

SCUBE2

INVASIONStromolysin 3Cathepsin L2

HER2GRB7HER2

GSTM1REFERENCE

Beta-actinGAPDHRPLPO

GUSTFRC

Best RT-PCR performanceand most robust predictors

CD68

BAG1

Paik et al, SABCS 2003


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Develop Recurrence Score (RS) Algorithm

RS = + 0.47 x HER2 Group Score- 0.34 x ER Group Score+ 1.04 x Proliferation Group Score+ 0.10 x Invasion Group Score+ 0.05 x CD68

- 0.08 x GSTM1- 0.07 x BAG1

RecurrenceCategory RS (0 100)

Low risk < 18

Intermediate risk 18 30

High risk 31


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0%

5%

10%

15%

20%

25%

30%

35%

40%

0 5 10 15 20 25 30 35 40 45 50

Recurrence Score

D i s t a n

t R e c u r r e n

c e a

t 1 0 Y e a r s

Low Risk Group High Risk GroupIntermediateRisk Group

My RS is 30, What is the chanceof recurrence within 10 yrs?

95% CI

Recurrence Score as a Continuous Predictor: Oncotype Dx Report

B14 Results: 668 patients


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B14-Results: 668 patientsDRFS Low, Intermediate, High RS Groups

Paik et al, SABCS 2003

0 2 4 6 8 10 12 14 16Years

0%

10%20%

30%

40%

50%60%

70%

80%

90%100%

D R F S

Low Risk (RS


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Other retrospective studies withouta predefined end point

MammaPrint (Amsterdam, Netherland) :- Microarray in Node-negative Disease May Avoid ChemotherapyTrial (partially funded by the European Commission)

Topo II (Topoisomerase II alpha):- Large meta-analysis of 4,500 patients from 4 large adjuvantprosepective trials with a centralized evaluation of both EGFreceptor 2 and Topo II status

- Trial of Principle trial: a prospective, neoadjuvant trial to validatethe biologic hypothesis of Topo II is a predictive marker ofresponse to anthracyclines


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2010 Breast Symposium: Plenary Lecture

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