059 bobolis lobular neoplasias ncbc 2014 · mass 15 19% type of lesion n % lcis 46/80 58% alh 34/80...

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National Consortium of Breast CentersLas Vegas, NVMarch 18, 2014

Kristie Bobolis, M.D.Medical Director

Breast Health CenterSutter Roseville

Lobular Neoplasia: What We Know NowMedical Oncology Perspective

Disclosures:

• Financial Disclosures

– None

• Off label usage

– Data for usage of aromatase inhibitors as preventive agents for breast cancer will be presented

Lobular Neoplasia: What We Know NowMedical Oncology Perspective

• Pathology Perspective– History lobular neoplasias and histologic features

• Radiology Perspective– Imaging features and screening strategies

• Surgical Perspective– Risk of breast cancer and surgical management

• Medical Oncology Perspective– Risk‐reducing agents for ALH, LCIS (ADH)

– Lifestyle modifications

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LOBULAR NEOPLASIA

“IMAGING OF”

Gary M. Levine M.D.

Director of Breast Imaging Associate Clinical Professor

Hoag Breast Care Center USC Keck School of Medicine

Newport Beach, CA. Los Angeles, CA.

SESSION #59

Lobular Neoplasia: What we Know Now

Disclosures:

Consultant: Hologic Inc.

Lobular Neoplasia

• Atypical Lobular Hyperplasia (ALH)

• Lobular Carcinoma in Situ (LCIS)

‐characterized by a proliferation of epithelial cells within lobules

‐ALH and LCIS differ only in the degree of acinar involvement

‐few acinar units are involved in ALH

‐entire lobules are involved in LCIS

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Lobular Neoplasia

• Atypical Lobular Hyperplasia (ALH)

• Lobular Carcinoma in Situ (LCIS)

‐First described by Foote and Stewart in 1941.

‐LCIS is a misnomer, not a true cancer.

‐Considered a risk factor for the subsequent development of in‐situ or invasive cancer in either breast.

‐ALH confers a 4‐5x relative risk for invasive breast cancer.

‐LCIS confers an 8‐10x relative risk for invasive breast cancer.

ALH and LCIS

Lack any distinct clinical or imaging findings!

Typically an incidental finding!!

ALH and LCIS

Lack any distinct clinical or imaging findings!

Typically an incidental finding!!

‐ discovered upon biopsy for suspicion of a different lesion.

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Lobular Neoplasia

QUESTION #1:

How are we Diagnosing Lobular Neoplasia?

Lobular Neoplasia

Hoag Breast Center – 5yr Experience(1/1/2008 thru 12/31/2013)

• # Cases of Lobular Neoplasia = 176

• # Dx w/ CNB = 101 (57%)

• # Dx w/ Surgical Excisional Bx = 75 (43%)

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Lobular Neoplasia


• # Total Breast Bx = 9,610

•# Core Needle Bx (MIBB) = 8,948 (93%)

• # Surgical Excisional Bx = 662 (7%)

Lobular Neoplasia

Conclusion #1:

A Diagnosis of Lobular Neoplasia is more common:

Surgical Bx >> CNB

‐more tissue is removed.

‐ often no specific lesion is targeted.

Lobular Neoplasia

Question# 2:

When Lobular Neoplasia is diagnosed thru CNB,

What type of lesion is targeted?

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Lobular Neoplasia Dx’d with CNB


• 101 cases of LN dx’d with CNB

• In 82 cases it was the sole/primary dx

• 10 cases were worked up at an outside facility

• 72 were imaged at Hoag and are linked with a specific imaging finding

Imaging Finding Which Prompted CNB (Leading to Dx of LN)

Lesion Description n %

Calcifications 42 58%

US Finding(mass, nodule, complex cyst, arch. distortion, duct ectasia)

17 24%

MRI Enhancmement 8 11%

Asymmetry 5 7%

Hoag Breast Center

n = 72

Imaging Guidance for CNB

Lesion Description Image Guidance # Cases Median # Cores

Calcifications Stereotactic 42 (58%) 8

Mass, complex cyst,Arch distortion, duct ectasia

Ultrasound 22 (31%) 4

MRI Enhancment M.R.I. 8 (11%) 7

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Memorial Sloan Kettering80 consecutive cases with LN in CNB underwent

surgical excision

MSKCC Cancer 2013;119:1073‐9

Type of lesion n %

Calcifications 48 60%

MRI enhancement 17 21%

Mass 15 19%

Type of lesion n %

LCIS 46/80 58%

ALH 34/80 42%

Lobular Neoplasia

Conclusion #2:

Most Common Imaging Finding Leading to a Dx of LN.

‐ Calcifications

‐ the Ca++ are indicative of another process (e.g. FCC)

Lobular Neoplasia

Question #3:

What is the Upgrade Rate at Hoag?

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Upgrade Rate at Surgical Excision

• 72 cases of LN dx by CNB

• 68 went on to Surgical Excision

• 18 (26%) were upgraded at surgery.

Lobular Neoplasia

Upgrade Rate at Hoag:

When a diagnosis of LN is made at CNB,

26% are upgraded at surgical excision

Conclusion #3

Modified From Murray et al. Cancer 2013;119:1073‐9

8%67%33%

Upgrade rates in the literature vary from 3 to 35%.

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Histologic Upgrade at Surgical Excision

Histology # % of Total

Invasive Lobular CA 8 45%

Invasive Ductal CA 3 17%

Invasive Mammary CA 1 5%

DCIS Hi Grade 3 17%

DCIS Low Grade 2 11%

Pleomorphic LCIS 1 5%

Pleomorphic LCIS

• An “advanced” form of LCIS.

•Higher degree of genomic instability than classic LCIS.

• Presents with Ca++ on a mammogram typical of hi grade DCIS.

•Has a worse prognosis than classic LCIS.

•Likely should be treated like hi grade DCIS with complete excision & RT.

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Lobular Neoplasia and Risk

• A diagnosis of LCIS is considered a marker for an increased

risk of breast cancer.

• The cancer can occur remote from the biopsy site.

• Ipsilateral or Contralateral breast.

• Relative Risk is 8‐12X.

• Absolute Risk is ~1%/yr.

MRI SCREENING

• MRI is highly sensitive for the detection of breast CA.

• Can allow detection of early breast CA otherwise occult.

• Patients diagnosed with LCIS are considered high risk.

•At Hoag they receive annual mammography and CEMRI.

• staggered by 6 months.

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Case 1:

56 y.o. female with history of left breast LCIS on CNB and surgical excisional bx in 2004.

8 mm spiculated mass RUOQ

Second Look Ultrasound is

Negative (Sono Occult)

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??? ???

Histology on MRI Guided CNB:

Grade II Invasive Ductal Carcinoma

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Questions?

[email protected]

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Lobular NeoplasiaPathology Perspectives

NCoBCLas Vegas, NV

March 8, 2014

Julio A. Ibarra, M.D.MemorialCare Breast Center at Orange Coast

Clinical Professor of Pathology, University of California, Irvine

History

• LCIS• Ewing 1919. Atypical acinar proliferation

• Foote and Stewart 1941. Lobular Carcinoma In Situ

• Muir 1941. Intralobular carcinoma

• ALH• Ackerman 1977; Azzopardi 1979

• Lobular Neoplasia-LN• Haagensen 1978. Lobular Neoplasia

• ALH/LCIS• Page et al 1985

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Foote and Stewart-1941

Muir 1941

Page 1985

Haagensen 1978

History

• Lobular Intraepithelial Neoplasia-LIN• Bratthauer, Tavassoli 2002

• Pleomorphic LCIS• Frost et al 1996

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Risk

• Marker of risk, Non-obligate precursor?

• ALH has a 4-5x relative risk • Either breast is at risk

• LCIS has a 8-11x relative risk in the first 15 years after a biopsy with LCIS• About 1-2% per year

• Either breast is at risk

• Nurses Health Study• Same risk for any degree of lobular atypia

• Not published data

LCIS

ALH

Along the duct

Signet ring

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LCIS with necrosis and calcification

pLCIS Histologic Features

• Architecture of regular LCIS, plus:• Nuclear pleomorphism

• Necrosis (comedo) can be present

• Calcification in the necrotic center

• Mitoses can be present

Differential Diagnosis ofpLCIS:

Duct Carcinoma In Situ

Most of the time the diagnosis can be established on H&E.

Core biopsies can be a problem.

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LCIS vs pLCIS vs DCIS

Classic LCIS pLCIS DCIS

Discovered Incidentally Mammography Mammography

Managmt post-core Surg Biopsy Excision Excision

Definitive treatment ObservationRisk reductionBilat mastectomy

Partial resect?Mastectomy

Partial resectMastectomy

Margin status Not pursued Aim for clear Aim for clear

Radiation Therapy No ? Yes

Mammography

• Looks like high grade DCIS

From Fadare et al. Am J Surg Pathol 2006(30):11;1445-53

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pLCIS vs DCIS

pLCIS DCIS

Loss of Cohesion Yes No

Intracytoplasmic Vacuoles

More common Less common

Pagetoid Ductal Involvement

More common Less common

Microacini Absent May be present

Associated classic LCIS More common Less common

Polarization of cells at periphery

Absent May be present

Credit to L. Collins & S Schnitt

Helpful stains

E-CadherinLoss of expression of the adhesion molecule E-cadherin is most commonly due

to mutation or deletion of CDH1 locus on chromosome 16q

P120 cateninLoss of expression of E-cadherin results in accumulation of p120 catenin in the

cytoplasm instead of the membrane.

Helpful stains

pLCIS HG DCIS

E-Cadherin Negative Positive

P120 catenin Cytoplasmic Membranous

Β-catenin Negative

HMWK Absent Present

Histology overrides stains.The presence of E-Cadherin positivity in a classic case of lobular carcinoma does not exclude the diagnosis.

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Prognostic markers of pLCIS

Classic LCIS pLCIS Apocrine pLCIS

ER + + 25%

P53 - 30% ?

Her2neu - - +

Ki67 Low High High

Genomic alterations(16q loss/1q gain)

Present Present Present and more numerous

LCIS and ALH are genetically similar.Some genetic alterations seen in LN are also seen in ILC

From Chen et al. Am J Surg Pathol 2009;33:1683-1694

Thank You

1

LCIS:Surgical Management Issues

Amy C. Degnim, MD, FACS

Associate Professor of SurgeryMayo Clinic, Rochester, MN

59 Lobular Neoplasia: What We Know Now

Financial Disclosures

NONE

OBJECTIVES

• Surgical issues related to LCIS

– Excision after core biopsy

– Excision at lumpectomy margins

– Longterm breast cancer risk

– Surgical risk reduction

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LCIS: Excision After Core Biopsy?

Rationale for Surgical Excision of HRL After Core Needle Biopsy

• Sampling error: sample of target lesion is not representative or is inadequate

Rationale for Surgical Excision of HRL After Core Needle Biopsy

• Sampling error: sample of target lesion is not representative or is inadequate

• Discordance: core biopsy histology does not match with expected findings, based upon the imaging appearance of the lesion

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Assessing Concordance

• Team approach

• Surgical excision is recommended when:– Concern that target lesion was missed

– Histology demonstrates high risk lesion in presence of a palpable or imaging mass lesion

– Findings are judged to be discordant

ASBrS Position Statement on Concordance August 15, 2011http://www.breastsurgeons.org/statements/PDF_Statements/Concordance_Assessment.pdf

Goals of Surgical Excision of HRL

• Remove biopsy site and original mammographic lesion

• Obtain a definitive diagnosis and exclude cancer

Goals of Surgical Excision of HRL

• Remove biopsy site and original mammographic lesion

• Obtain a definitive diagnosis and exclude cancer

• How often does core biopsy of LCIS miss cancer?

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Upgrade rates after core biopsy of LCIS

LCISSeries # # excised % CA

Renshaw et al 2006 115 52 4%

Shah‐Khan et al 2012 20 20 5%

Cangiarella et al 2008 20 20 10%

Margenthaler et al 2006 16 16 19%

Liberman et al 2000 16 14 22%

Brem et al 2008 100 67 25%

Shin and Rosen 2002 NA 8 25%

Zhang et al 2001 10 10 30%

Elsheik and Silverman 2005 14 13 31%

Foster et al 2004 15 12 33%

Lechner et al 1999 89 58 34%

Mahoney et al 2006 14 10 40%

Londero et al 2008 21 20 60%

Adapted from Cangiarella J et al. Arch Pathol Lab Med 2008; 132:979‐83Hussain M et al. EJSO 2011; 37:279‐89

Upgrade rates after core biopsy of Lobular Neoplasia

Lobular Neoplasia (LCIS or ALH)

Series # # excised % CA

Yeh at al, 2003 22 15 8%

Bauer et al, 2003 13 7 14%

Middleton et al, 2003 35 17 35%

Lavoue et al, 2007d 70 42 19%

Purdie et al, 2010 50 47 21%

O’Neil et al, 2010 45 27 19%

Menon et al, 2008 44 25 36%

Lee et al, 2003 18 13 46%

El‐Sayed et al, 2003 33 33 33%

Houssami et al, 2007 23 23 61%

Dillon et al, 2007 12 9 44%

Upgrade After Core Biopsy of LCIS

Limitations of most published series …

• LCIS and ALH often grouped together

• Not all patients have excision (selection bias)

• Cases of radiographic/pathologic discordance often not excluded

• Presence of other HRL in core biopsies often not accounted for

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Summary- Excision of LCIS after core biopsy

• PLCIS- YES, excise

• “Classic” LCIS- safe answer is Excision

– but controversial

• Consider observation (no excision):– Radiologic-pathologic concordance

– No mass or soft tissue density

– No associated high risk lesion

– LCIS was incidental- not associated with the targeted imaging lesion

LCIS at Lumpectomy Margins: Does it need to be excised?

Study Years F/U LCISabsent

LCIS present

P value

Abner2000

1968-1986 8 yrs 12%127/1062

13%15/119

NS

Sasson2001

1979-1995 6 yrs 5%57/1209

15%10/65

0.001

Ciocca2008

1980-2007 6 yrs 3.8%98/2604

4.5%13/290

NS

Impact of LCISon Risk of IBTR after BCT

Abner Cancer 2000;88:1072-7Sasson Cancer 2001;91:1862-9

Ciocca AnnSurgOnc 2008;15(8):2263-2271

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Study Years F/U LCISabsent

LCIS present

P value

Abner2000

1968-1986 8 yrs 12%127/1062

13%15/119

NS

Sasson2001

1979-1995 6 yrs 5%57/1209

15%10/65

0.001

Ciocca2008

1980-2007 6 yrs 3.8%98/2604

4.5%13/290

NS

Impact of LCISon Risk of IBTR after BCT

Sasson et al – 22% of pts had positive or unknown margin status

Ciocca et al – No difference in IBTR if LCIS present/ absent at the surgical margin Abner Cancer 2000;88:1072-7

Sasson Cancer 2001;91:1862-9Ciocca AnnSurgOnc 2008;15(8):2263-2271

LCIS at the margin:Pleomorphic vs “Classical” LCIS

Pleomorphic “Classical”

Middleton LT et al. Am J Surg Pathol 2000; 24(12):1650-6Bentz JS et al. Mod Pathol 1998:11(9): 814-22

Re-excise

No FurtherSurgery

LCIS: Longterm Breast Cancer Risk

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• Diffuse pattern

– Multifocal in over 50% of cases

– Bilateral in 30%

• Increased risk for development of invasive ca

– 1% per year, steady over time

– Later cancers: ~50% IDC, ~50% ILC

Urban, Cancer 1967 Wheeler, Cancer 1974 Andersen, Cancer 1977Haagensen, Cancer 1978 Rosen, Ann Surg 1979 Rosen, Cancer 1981Page, Hum Pathol 1991 Chuba, J C Oncol 2005 Abdel‐Fatah, AmJSurgPath2007 Karabakhtsian , Am J Surg Path 2007 Purdie, J Clin Path 2010

Lobular Neoplasia

Mean f/u

Ipsilateral cancer

Contralateral cancer

Rosen 1978 24 yrs 18/83 (22%) 17/83 (20%)

Haagensen 1983

15yrs 27/257 (11%) 26/257 (10%)

LCIS: Longterm Cancer RiskIpsilateral and Contralateral

Fisher ER et.al. Cancer 2004;100:238-44

LCIS: Longterm Cancer RiskIpsilateral and Contralateral

F/U Ipsilateral CA Contralateral CA

7 studies (1974-1993)

n=610

14 yrs

(5-24)

12%

(74/602)

9%

(37/610)

Fisher (2004)

n=18012 yrs

9%

(16/180)

8%

(14/180)

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Fisher ER et.al. Cancer 2004;100:238-44

F/U Ipsilateral CAContralateral

CA

7 studies (74-93)

n=610

14 yrs

(5-24)0.9% per yr 0.6% per yr

Fisher (2004)

n=18012 yrs 0.8% per yr 0.7% per yr

LCIS: ANNUAL Cancer RiskIpsilateral and Contralateral

LCIS: MSKCC data~2% annual hazard for breast cancer

95% CI

Time without cancer S.E. lower upper

1 year 0.98 0.005 0.970 0.990

2 year 0.96 0.007 0.946 0.974

3 year 0.94 0.009 0.922 0.958

4 year 0.93 0.011 0.908 0.952

5 year 0.91 0.011 0.888 0.932

6 year 0.9 0.012 0.876 0.924

Unpublished data; Courtesy of Dr. Tari King et al. MSKCC 2011

Summary: Longterm BC Risk for LCIS

• Relative Risk: 10-12X

• Absolute risk:• 20-25% “lifetime”• ~1% per year (maybe higher?)• Steady over time

• Ipsilateral risk ~ contralateral risk

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LCIS: Longterm Management Options

• High Risk Surveillance– Early detection

• Surgical risk reduction- 90-95% reduction– Bilateral mastectomy

• Prevention therapies: ~50% reduction

LCIS: Surgical Risk Reduction

Efficacy of Bilateral Mastectomy

• Reduces breast cancer risk 90-95%, not 100%

• Hartmann et al: 639 women with family history

• Median f/u 14 years

• Cancer events after BPM compared to Gail predictions and events in sisters

• 90-95% reduction in BC risk

Hartmann et al. NEJM 1999;340:77-84Domchek et al. JAMA 2010;304(9):967-75

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• Domchek et al: prospective study- BRCA+

• At 3 years f/u

• 0 cancers in 247 women with BPM

• 98 BCs in 1372 women without BPM (7%)




• Not proven to improve survival




• Not proven to improve survival- Why not??


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• Not proven to improve survival- Why not??

• Not all women will develop cancer

• Most breast cancers can be detected early

• Most breast cancers can be treated successfully


Safety of Nipple-Sparing Mastectomy?

• Hartmann et al. 14 year f/u

• 639 women with FH and bilateral mastx

• 575 subq mastx 7 CA (1.2%)

• 64 NAC removed 0 CA p=0.38

• Only 1/7 cancers occurred in NAC (0.2%)

• Modern NSM leaves less tissue than subqmastx

Hartmann et al. NEJM 1999;340:77-84

Safety of Nipple-Sparing Mastectomy?

• Review of NSM studies (prophy+cancer)

• 17 studies reported on local recurrence and NAC recurrence

• Median f/u: 6 mths- 12 years (most ~2 yrs)

• 3241 patients; LR: 0 -11.7%

• NAC recurrence: 13/3241 = 0.4%

Tokin et al. Int J Surg Onc 2012;ID921821

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Longterm Satisfaction after BPM

• 572 women with 14.5 yr f/u after BPM 1960-1993

Frost et al. JAMA 2000;284(3):319-24

CON• Worse body image- 36%• Diminished femininity- 25%• Impaired sexuality- 23%

PRO• Less worry of BC

74%

Considering Bilateral PM ?

• Pre-op Counseling– breast surgeon: efficacy of PM- not 100%

risks of PM alternatives

– plastic surgeon: reconstruction options realistic cosmetic outcomes potential complications

– insurance issues– mental health professional:

impact on body image motivating factors/fearsmental status

Summary: Surgical Risk Reduction

• Main benefits:– Reduces BC risk 90-95%– Reduces worry of BC

• Does not prolong survival

• Can have detrimental effects on body image and sexuality

• Careful counseling is mandatory

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Thank You

[email protected]

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Established Breast Cancer Risk Factors

• Gender

• Age

• Family history

• Hereditary syndrome

• Thoracic radiation

• Mammographic density

• Benign breast disease

– ADH, ALH, LCIS

• Reproductive factors

• Endogenous hormones

• Exogenous hormones

• Breast feeding

• Lifestyle

– Obesity

– Physical activity

– Alcohol

www.NCCN.org: Guidelines for Breast Cancer Risk Reduction

Risk Factors for Development of BreastInterplay of Genes and Environment

Risk Factors for Development of Breast:Age

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Family History and Breast Cancer Risk

• 1 first degree relative

– 2 fold increased risk

• 2 first degree relatives

– 3 fold increased risk

• 3+ first degree relatives

– 4 fold or more

• Age at diagnosis

– Impacts risk

Rahman Nature January 2014

Cancer Predisposition Genes

Mammographic Density: Effect on Imaging and Breast Cancer Risk

Boyd Classification 1995

Impacts effectiveness of screeningCharacter of tissue comprising dense breast associated with increased risk

2/3 of premenopausal women; 25% of perimenopausal women; 50% of postmenopausal women on HRT

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High Number of Menstrual Cycles: Associated with Breast Cancer Risk

M Pike Oncogene 2004

Early menarcheRR 1.2 ‐ 1.5

Late menopause

E2

Progesterone

Exogenous Hormones and Breast Cancer Risk

• HRT (E+P) use shortly after menopause breast cancer risk during use and soon after

• Combined HRT RR is 1.5‐2.0

• Risk decreases after stopping

• No Long Term Effect on Risk

Chlebowski1 NEJM 2009

During Intervention Post‐intervention

HR=1.26 (1.02‐1.55) HR=1.27(0.91‐1.72)

Breast Cancer Risk Associated with HRT and Mammographic Density

• Increase in postmenopausal MD (BI‐RADS 3/4) with HRT. 1

• Breast cancer risk high among women with very high MD on HRT.2

(4.2% 5y risk vs 2.4% in non users)

• Risk of advanced stage breast cancer 1.7 fold for women on HRT with very high MBD compared to average MBD.2

Chlebowski1 JAMA 2010Kerlikowske2 JCO 2010

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Alcohol Consumption and Breast Cancer Risk

• Use of Alcohol is linked to an increased risk of breast cancer.

• Consuming 1 drink per day may result in a small risk.

• Consuming 2 or more drinks per day increases risk 1.5 times that of women who abstain.

American Cancer Society

Obesity and Breast Cancer Risk

• Obesity increases risk of post‐menopausal breast cancer.

• 50% increase in risk for high vs. low measures of anthropometry.

• Risk increases with BMI increases.

• Population attributable fraction: – RR 1.5 for obese women 22.6% of postmenopausal breast cancer can be attributed to obesity.

Obesity/Metabolic Syndrome and Cancer Risk

• Link between obesity and cancer risk may be related to subclinical inflammation

• Macrophages infiltrate around necrotic adipocytes to form crown‐like structures. (CLS)

• Inflammatory cytokines contribute to induction of aromatase in adipose tissue

Berger JCO 2010 P Morris ASCO Breast 2012 Cinti S Am J Physiol Endocrinol Metab 2009

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Physical Activity and Breast Cancer Risk

• Lowers breast cancer risk by 25% – Lifetime activity of at least moderate intensity

• Intensity– Moderate activity: 15% reduction

– Vigorous activity: 18% reduction

• Duration– 2‐3 hours/week: 7%

– 6.5+ hours/week: 28%

• Timing– Activity during 20s: 8%

– Activity >50 years: 17%

– Adult lifetime: 27%

1. Lynch, Friedenreich, Physical Activity and Cancer. Springer 2011

Benign Breast Disease: ADH, ALH, LCIS and Breast Cancer Risk

• Several large population based studies1

– ADH, ALH increase breast cancer risk 4‐5 fold

– LCIS carries higher risk 8‐10 fold

• Some differences as to factors influencing breast cancer risk2

– Younger age

– Multiple foci; extent of atypia

– Time after biopsy

– Type of atypical hyperplasia (ALH vs ADH)3

– Family history1 Nashville 1995, Mayo 2005, NHS 20062 Hartmann Cancer Prev Res 2014; 3 Coopey 2011

Biologic Characterization of Premalignant Lesions

Normal Atypical hyperplasia Carcinoma in situ Invasive Carcinoma

Chromosomal changes

LOH: 1p, 2p, 3p, 6q, 8p, 9p, 11p, 13p, (16q) …Gains: (1q), 8q,24, 17q 12, 20p, 22q

LOH: 7p, 10q, 18p, 22q

Epigenetic changes(Methylation)

CDH1, HIN‐1, RARβ, Cyclin‐D2, TwistCell cycle reg, Hormone reg, adhesion, angiogenesis, Growth inhibition

RASSF1A, DAP

Gene expressions changes

Chemokines, SOD‐2, HIN‐1, LIF, Ikα, TFF3, FASN, IFI6‐16, pS2, C‐FOS, CCND1, p53, MycHer‐2; MMP‐9, Down‐reg claudin 4

IGF‐BP7, PIP5KB, GAPDH, APOBEC1

Normal Hyperplasia Atypia In Situ

Basement membrane

MyoepithelialLayer

EpithelialProlif

1 Harris Nature Genetics 2013; 2 Shin Hum Pathol 2013; 3 GarnisMolec Ca 2004

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Gene Expression Profiles in LCIS

• Traditionally viewed as marker of breast ca risk1,2

• Recent clinical, path, genetic analysis support ALH, LCIS as precursors of invasive breast ca3,4,5.

• Global gene expression profiling LCIS vs normal:– Down regulation of claudin 4

– Overexpression of matrix metalloproteinase 9

• Florid LCIS, pleomorphic LCIS– Shares features with classic LCIS: E‐cad loss; lobular genetic signature of 1q gain and 16 q loss

– Increased genetic complexity

1Wheeler Cancer 2004; 2 McDivitt JAMA 1967; 3 Page Lancet 2003;4 Cao, Polyak Breast Ca Res 2008; 5 Hartmann Cancer Prev Res 2014

Sinn J Mol Med 2009

Progression Model of Breast Cancer Precursor Lesions

DCISADH

IDC

Progression of precursor lesions: complex interplay of epithelial cell, microenvironment

and host

• Precursor lesions display genetic and molecular alterations……..not all progress

– ADH or ALH (RR 4‐6): Absolute risk 15‐20%

– LCIS (RR 8‐10): Absolute risk 20‐25%

• Microenvironment also displays dramatic changes

• Host factors (age, genetic factors, HRT)

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Approaches to Risk Reduction in Women with Lobular Neoplasia

Life‐style

Exogenous hormones

Alcohol consumption

Physical activity

Diet and nutrition

BMI

Preventive Therapy

Surgery

SERMS:

– Tamoxifen (NSABP P1)

– Raloxifene (STAR P2)

Aromatase Inhibitors:

– Exemestate (MAP.3)

– Anastrazole (IBIS‐II)

Stratifying Risk

0

10

20

30

40

50

60

<0.5 1.0‐2.0 2.0‐4.0 4.0‐10 >10

% of Population

% of Cancer

65% of population Low‐modest risk35% of breast cancer

35% of populationModerate‐high risk60% of breast cancer

ALH*, ADHALH*, ADH

LCIS*, CPGLCIS*, CPG

High risk CPG

High risk CPG

0.5% of populationVery high risk5% of breast cancer

Risk Reducing Agents

• Tamoxifen (SERM) for Risk Reduction

– Early Breast Cancer Trialists’ meta‐analysis

– NSABP BCPT (P‐1)

– International Breast Cancer Intervention Study (IBIS‐I)

• Raloxifene (SERM) for Risk Reduction

– MORE Trial/ CORE Trial

– STAR Trial (P2)

• Aromatase Inhibitors

– ATAC Trial/ Breast International Group (BIG) 1‐98

– NCI of Canada (CTG) MAP.3

– IBIS‐II

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Risk Reducing Agents: NSABP‐P1

• 13,338 healthy women 60 or older, aged 35 to 59 with a 1.7% or greater 5 year risk for developing breast ca* or hx of LCIS randomized Tamoxifen vs placebo

• Tamoxifen decreased risk for invasive breast ca by 49%; noninvasive by 50%– Reduced risk for invasive breast ca by 86% in participants with ADH and 66% for LCIS.

– Decrease in bone fractures

*Using modified Gail model

Rates of Breast Cancer in the NSABP (P‐1) Breast Cancer Prevention Trial

Patient Characteristic Risk Ratio (Tamoxifen vs Placebo)

95% CI

All women (invasive) 0.51 0.39‐0.66

Age < 49 y 0.56 0.37‐0.85

Age 50‐ 59 y 0.49 0.29‐0.81

Age > 60 y 0.45 0.27‐0.74

History of LCIS 0.44 0.16‐1.06

History of ADH 0.14 0.03‐0.47

ER+ 0.41

All women (noninvasive) 0.50 0.33‐0.77

Fisher et al, JNCI 1998

Tamoxifen Toxicity: Experience in NSABP P‐1

• Hot flashes, invasive endometrial cancer in postmenopausal women, and cataracts.

• Significant increase in the incidence of PE observed in women 50 and older taking tamoxifen.

• No differences observed in overall rates of mortality among treatment groups.

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Tamoxifen Toxicity: Experience in NSABP BCPT

Toxicity Placebo Tamoxifen Risk Ratio 95% CI

Endometrial Ca <49 y 1.09 1.32 1.21 0.41‐3.60

>50 y 0.76 3.05 4.01 1.70‐10.9

DVT <49 y 0.78 1.08 1.39 0.51‐3.99

>50 y 0.88 1.51 1.71 0.85‐3.58

Stroke <49 y 0.39 0.30 0.76 0.11‐4‐49

>50 y 1.26 2.20 1.75 0.98‐3.20

PE <49 y 0.10 0.20 2.03 0.11‐119.62

>50 y 0.31 1.00 3.19 1.12‐11.15

Bone fracture <49 y 2.24 1.98 0.88 0.46‐1.68

>50 y 7.27 5.76 0.79 0.60‐1.05

Ischemic heart disease 2.37 2.73 1.15 0.81‐1.64

Cataracts developed 21.72 24.8 1.14 1.01‐1.29

Cataract surgery 3.00 4.72 1.57 1.16‐2.14

Annual rate per 1000 patients Fisher et al JNCI 1998

Tamoxifen Recommendations:NCCN Guidelines

• Recommended as an option to reduce breast cancer risk in healthy pre and post‐menopausal women who have a 1.7% or greater 5 year risk for breast cancer* or who have had LCIS.

• Risk/benefit ratio for tamoxifen in post‐menopausal influenced by age, presence of uterus, other co‐morbid conditions.1

Using modified Gail model*

Raloxifene for Risk Reduction

• Raloxifene is a second‐generation SERM with similar anti‐estrogenic effects with less endometrial stimulation.

• FDA‐approved for reducing risk of fractures in women with osteoporosis

• Efficacy as a breast cancer risk reduction agent has been evaluated in several clinical studies.

• FDA (2007) expanded indications for raloxifene– reduction in risk of invasive breast cancer in high risk postmenopausal women

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Raloxifene for Risk Reduction

Risk Reduction Breast Ca

MORE:

7705 postmenopausal women with osteoporosis3 yr of 60 mg; 120 mg or placebo

Designed to determine if 3y of raloxifene reduced risk of fracture; Reduced vertebral fracture; increased BMD femoral neck and spines

RR of invasive breast cancer was 0.24 at 40 mos

ER+ cancer markedlyreduced (RR 0.10)

CORE: Designed to assess the effect of 4 additional years of ralox on incidence of IBC

Incidence of IBC reduced by 59%

ER+ cancer reduced by 66%

MORE + CORE:

4,011 postmenopausalwomen with osteoporosis

Combined results over 8 year of trials

RR of invasive breast reduced by 66%

ER+ cancer reduced by 76%

Raloxifene Adverse Events: MORE and CORE Trials

• Hot flashes, flu‐like symptoms, leg cramps

• DVT (0.7% v 0.2%) raloxifene v placebo (MORE)

• PE (1% v 0.3%) raloxifene 120 mg/d (MORE)

• No statistical significant difference in endometrial bleeding, hyperplasia and cancer between raloxifene vs placebo

• No increase in cataracts vs placebo (MORE)

STAR Trial: NSABP P‐2

• 19,747 postmenopausal women 35 y or older at increased risk for breast cancer* randomized to Tamoxifen v Raloxifene

• Primary endpoint: invasive breast cancer• Secondary endpoints: QOL, incidence of DCIS, DVT, PE, endometrial ca, stroke, cataracts, and death.

• At 4 years of follow‐up:– Equally effective at reducing IBC– Raloxifene not as effective as tamoxifen in reducing risk of DCIS

*Using modified Gail Model

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STAR Trial: Updated 8 year Follow‐Up

• Raloxifene approx 76% as effective as tamoxifen in reducing risk of invasive breast ca.

• With longer f/u, risk of DCIS with raloxifene group grew closer to that observed for tamoxifen.

• Raloxifene remained as effective as tamoxifen in reducing risk of invasive ca for LCIS.

• Raloxifene less effective than tamoxifen for ADH.

• No significant differences in mortality.

Vogel Cancer Prev Res 2010

Rates of Breast Cancer in The STAR Trial at 81 Months Median Follow‐Up

Patient Characteristic Risk Ratio (Ralox v Tamox) 95% CI

All Women (invasive) 1.24 0.10 – 1.47

<50 y 1.53 0.64 – 3.80

50 – 59 y 1.23 0.97 – 1.57

>60 y 1.22 0.95 – 1.58

History of LCIS 1.13 0.76 – 1.69

History of ADH 1.48 1.06 – 2.09

All Women (noninvasive) 1.22 0.95 – 1‐59

Vogel VG, Constantino JP, Wickerham DL: Cancer Prev Res 2010

Toxicity Experience in Women Enrolled in STAR Trial‐ 81 Month Follow‐Up

Toxicity Tamoxifen Raloxifene Risk Ratio (Ralox v Tamox)

95% CI

Invasive endometrial ca 2.25* 1.23 0.55 0.36 ‐ 0.83

Endometrial hyperplasia 4.40 0.84 0.19 0.12 – 0.29

Hysterectomy during f/u 12.08 5.41 0.45 0.37 – 0.54

Thrombo‐embolic events 3.30 2.47 0.75 0.60 – 0.93

DVT 1.93 1.38 0.55 0.54 – 0.95

PE 1.36 1.09 0.27 0.57 ‐ 1.11

Cataracts during f/u 14.58 11.69 0.80 0.72 – 0.89

Cataracts / underwent sx 11.18 8.85 0.79 0.70 – 0.90

*Annual rate per 1000 patients Vogel VG Caner Prev Res 2010

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Raloxifene Recommendations: NCCN Guidelines

• Recommended as an option to reduce breast ca risk in healthy post‐menopausal women who have a 1.7% risk or greater 5 y risk for breast cancer* or who have LCIS.

• Risk/benefit for use in post‐menopausal women influenced by age and co‐morbid conditions.

• No data for use in premenopausal women or age younger than 35.

*Using modified Gail Model

Freedman A N et al. JCO 2011;29:2327-2333

Benefit/risk Indices for tamoxifen and raloxifene chemo-prevention for caucasian women 50 or older (with uterus)

Benefit/risk Indices for tamoxifen and raloxifene chemo-prevention for caucasian women 50 or older (without uterus)

Freedman A N et al. JCO 2011;29:2327-2333

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Aromatase Inhibitors for Risk Reduction

• ATAC trial and BIG 1‐98 trials (Tamoxifen vs AI)– Contralateral second breast primary reduced

– Benefit persists beyond 5 years

• Exemestane vs placebo– MAP‐3 prevention trial1 showed substantial risk reduction compared to placebo (HR 0.35)

• Anastrazole vs placebo– IBIS II prevention trial2 showed substantial risk reduction compared to placebo (HR 0.47)

1. PE Goss NEJM 20112. Cuzick Lancet 2013

Exemestane for Breast Cancer Prevention in Postmenpausal Women1

1. PE Goss NEJM June 6, 2011NCIC CTG MAP.3 Study

Exemestane toxicity on MAP‐3Side Effects Exemestane N=2440 Placebo N=2248 P‐value

Any 1963 (88%) 1901 (85%) 0.003

Hot flashes 900 (40%) 718 (32%) <0.001

Fatigue, sweating, insomina

Diarrhea 118 (5%) 75 (3%) 0.002

Joint and Muscle pain 665 (30%) 606 (27%) 0.04

Vaginal dryness 352 (16%) 343 (15%) 0.68

Secondary end pt toxic effects

Fracture 149 (6.7%) 143 (6.4%) 0.72

New osteoporosis 37 (1.7%) 30 (1.3%) 0.39

Cardiovascular events 106 (4.7%) 111 (4.9%) 0.78

1. PE Goss NEJM June 6, 2011

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IBIS‐II: Anastrozole for prevention of breast cancer in high risk postmenopausal women

Cuzick Lancet December 2013

AnastrozoleN=1920

PlaceboN=1944

Hazard Ratio

All invasive ca 32 (2%) 54 (3%) 0.50 (0.32‐0.76)

Invasive ER+ 20 (1%) 47 (2%) 0.42 (0.25‐0.71)

Invasive ER‐ 11 (1%) 14 (1%) 0.78 (0.35‐1.72)

DCIS 6 (<1%) 20 (1%) 0.30 (0.12‐0.74)

All 40 (2%) 85 (2%) 0.47 (0.32‐0.68)

Adverse Events Reported IBIS‐IIAnastrozoleN=1920

Placebo N=1944

Risk Ratio

Fractures 164 (9%) 149 (8%) 1.11 (0.90‐1.38)

Musculoskeletal 1226 (64%)* 1124 (58%) 1.10 (1.05‐1.16)

Vasomotor 1090 (57%)* 961 (49%) 1.15 (1.08‐1.22)

Gynecological 460 (24%) 423 (22%) 1.10 (0.98‐1.24)

Vascular 152 (8%) 127 (7%) 1.27 (0.97‐1.52)

Eyes 348 (18%) 355 (17%) 1.05 (0.92‐1.21)

Any 1709 (89%) 1723 (89%) 1.00 (0.98‐1.03)

IBIS‐II Summary

• Follow‐ up longer than MAP.3 prevention trial.

• Results similar to MAP.3 with AI’s appearing more effective than SERMS in high risk postmenopausal

• Most of the side effects associated with estrogen deprivation were not attributable to treatment. – Vasomotor and musculoskeletal side effects reported

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Summary: Risk Reducing AgentsSERMS (FDA approved for prevention)

• Tamoxifen (P‐1)

– Invasive breast ca risk reduced by 49%, DCIS by 50%

– ER+ breast ca reduced by 69%

– ADH: Tamoxifen reduced breast ca risk by 86%

– LCIS: Tamoxifen reduced risk by 56%

– Risk benefit ratio favorable for premenopausal

• Raloxifene (P‐2) almost as effective as Tamoxifen

– Reduced risk for both IBC 76% and DCIS 78%

– Risk benefit ratio favorable for postmenopausal

Summary: Risk Reducing Agents:Aromatase Inhibors (AI’s)

• AI’s are also quite effective at preventing breast cancer with reasonable risk benefit ratio for postmenopausal women without osteoporosis.

• Exemestane: (MAP.3) breast ca risk reduced 65%

• Anastrozole (IBIS‐II) breast ca risk reduced 53%

– Reduction in ER+ breast cancer 58%

• Approved for invasive breast cancer

• FDA approval as preventive agents, not yet sought

Limitations of Risk Reducing Therapy

• Do not appear to significantly reduce risk of ER negative breast cancer.

• Primarily reduce the incidence of ER+ breast cancer (not by 100%)

• Toxicity:

– Venous thromboembolism, invasive uterine cancer, musculoskeletal effects and hot flahses

• Important to individualize

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Discussion of Lifestyle Recommendations

• Maintain a normal weight

• Remain physically active

• Avoid postmenopausal HRT

• Keep alcohol intake low

059 bobolis lobular neoplasias ncbc 2014 · mass 15 19% type of lesion n % lcis 46/80 58% alh 34/80...

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