HIGHLIGHTS ON BREAST CANCER Eyad Alsaeed MD, FRCPC. Consultant Radiation Oncologist Acting Chairman...

HIGHLIGHTS ON BREAST CANCER

Eyad Alsaeed MD, FRCPC.

Consultant Radiation Oncologist Acting Chairman of Radiation OncologyPrince Sultan Hematology @ Oncology centerKFMC

Breast Cancer In KSASaudis

676 new cases among women (3317) in 2003 16 new cases among men (3327) in same year 1st ca among women (20.8%) 1st of all ca 10.6% all 6516 ca cases among both

genders ASR 13.9/100000

– Eastern 27.6/100000– Makkah 19.1/100000– Riyadh 16.2/100000– Northern 15.5/100000– Jouf 14.6/100000

Mean age at diagnosis was 48y (19-98)SAUDI NCR REPORT 20033

Cancer Incidence for Most Common Sites Cancer Incidence for Most Common Sites (2004)(2004)

CancerCancer MalMalee

FemalFemalee

All All %%

Breast Breast 1515 783783 798798 11.511.5

CRCCRC 366366 281281 647647 9.39.3

NHLNHL 332332 224224 556556 8.08.0

LeukemiaLeukemia 241241 194194 435435 6.26.2

ThyroidThyroid 8787 328328 415415 6.06.0

LiverLiver 231231 9393 324324 4.64.6

LungLung 233233 6363 296296 4.24.2

HDHD 166166 9898 264264 3.83.8

SkinSkin 136136 125125 261261 3.73.7

Brain, Brain, CNSCNS

147147 100100 247247 3.53.5

ProstateProstate 214214 -- 214214 3.13.1

StomachStomach 141141 7070 211211 3.03.0

BladderBladder 160160 4141 201201 2.92.9

UterusUterus -- 117117 117117 1.71.7

OvariesOvaries -- 108108 108108 1.51.5

All OthersAll Others 10091009 866866 18751875 26.926.9

TotalTotal 34783478 34913491 69606960 100100

Country Country Breast caBreast ca All F ca All F ca %%

KSAKSA 534534 26772677 20.3%20.3%

KuwaitKuwait 9797 327327 29.7%29.7%

BahrainBahrain 8888 204204 43.4%43.4%

QatarQatar 1717 9090 18.9%18.9%

UAE UAE 4747 186186 26%26%

OmanOman 7474 419419 17.7%17.7%

Gulf Cancer Registry 2001 DataGulf Cancer Registry 2001 Data

Age of BC Females Cases in Selected Arab Countries

Breast Cancer Global View Breast Cancer Global View

Total No.Total No. 13018613018677

11stst Women Ca Women Ca

No. Ca DeathsNo. Ca Deaths 464854464854 22ndnd cause of ca cause of ca deaths deaths

Developed Developed Countries Countries

679682679682 11stst Women Ca Women Ca

Developed Developed CountriesCountries

203528203528 22ndnd cause of ca cause of ca deaths deaths

Developing Developing CountriesCountries

593233593233 11stst Women Ca Women Ca

Developing Developing CountriesCountries

255576255576 22ndnd cause of ca cause of ca deaths deaths Global Cancer Facts & Figures Report (2007)American Cancer

Society

Breast Cancer Global ViewBreast Cancer Global View

Incidence Rates varies By 25-30 Incidence Rates varies By 25-30 folds from as low as 3.9/100000 in folds from as low as 3.9/100000 in Mozambique to 10.1/100000 in USA Mozambique to 10.1/100000 in USA (2002)(2002)

This variation can be attributed to This variation can be attributed to under reporting as well as many under reporting as well as many factors are of importancefactors are of importance

Global Cancer Facts & Figures Report (2007)American Cancer Society

Breast cancer mortalityBreast cancer mortality(1980-2007)(1980-2007)

Histopathologic Subtypes

Morphology Total %

Infiltrating duct carcinoma (IDC) 518 76.6%

Lobular carcinoma 33 4.9%

Carcinoma, 20 3.0%

IDC mixed with other types of carcinoma 17 2.5%

Infiltrating duct & Lobular carcinoma 14 2.1%

Adenocarcinoma 13 1.9%

Medullary carcinoma 12 1.8%

Paget disease & Infiltrating duct carcinoma

10 1.5%

Infiltrating duct carcinoma (IDC) 7 1.0%

All Others 32 4.7%

SAUDI NCR REPORT 20033

Stage Distribution 2003

11.7% 15.5%

50.0% 22.8%Regional Localized

Distant Unknown

SAUDI NCR REPORT 20033

Breast Cancer Facts

BC is most common lethal cancer in women.

2nd leading cause of death

BC is most common lethal cancer in women.

2nd leading cause of death

One out of eight women will be diagnosed with breast cancer

One out of eight women will be diagnosed with breast cancer

All women are at risk

Incidence increases with age

All women are at risk

Incidence increases with age

BREAST CANCER RISK FACTORS BREAST CANCER RISK FACTORS

FACTORS THAT CAN NOT BE CHANGED:FACTORS THAT CAN NOT BE CHANGED:AgeAgeRace Race Menstrual HistoryMenstrual History (<12 & >50)(<12 & >50)

Reproductive HistoryReproductive History (1(1stst child after 30 child after 30 y/40%)y/40%)

Family/Personal HistoryFamily/Personal History Genetic FactorsGenetic FactorsRadiationRadiation Treatment with DESTreatment with DES (35%)(35%)

FACTORS THAT CAN NOT BE CHANGED:FACTORS THAT CAN NOT BE CHANGED:AgeAgeRace Race Menstrual HistoryMenstrual History (<12 & >50)(<12 & >50)

Reproductive HistoryReproductive History (1(1stst child after 30 child after 30 y/40%)y/40%)

Family/Personal HistoryFamily/Personal History Genetic FactorsGenetic FactorsRadiationRadiation Treatment with DESTreatment with DES (35%)(35%)

70% of cases have no risk factors70% of cases have no risk factors

BREAST CANCER RISK FACTORS BREAST CANCER RISK FACTORS

FACTORS THAT CAN BE Controlled:FACTORS THAT CAN BE Controlled:

Obesity Obesity (postmenopausal obesity)(postmenopausal obesity) Exercise Exercise (60%)(60%)

Alcohol Alcohol (2-5 drinks/1.5 )(2-5 drinks/1.5 )

Breast Feeding Breast Feeding (1.5-2 years / 50%)(1.5-2 years / 50%)

Hormone Replacement Therapy Hormone Replacement Therapy ((slightslight))

Birth Control Pills Birth Control Pills (slight/?)(slight/?)

Not having children Not having children

FACTORS THAT CAN BE Controlled:FACTORS THAT CAN BE Controlled:

Obesity Obesity (postmenopausal obesity)(postmenopausal obesity) Exercise Exercise (60%)(60%)

Alcohol Alcohol (2-5 drinks/1.5 )(2-5 drinks/1.5 )

Breast Feeding Breast Feeding (1.5-2 years / 50%)(1.5-2 years / 50%)

Hormone Replacement Therapy Hormone Replacement Therapy ((slightslight))

Birth Control Pills Birth Control Pills (slight/?)(slight/?)

Not having children Not having children

Risk Factors by CategoryRisk Factors by Category High RiskHigh Risk

> 4 times> 4 timesModerate RiskModerate Risk

2- 4 times2- 4 times slight Risk slight Risk

1-2 times1-2 times

▪▪ FemaleFemale

▪▪ Age (>50)Age (>50)

▪▪ Country of birth in North Country of birth in North America, North EuropeAmerica, North Europe

▪▪ Personal history of prior Personal history of prior Beast CancerBeast Cancer

▪▪ Family history, bilateral, Family history, bilateral, premenpausal, or familial premenpausal, or familial cancer syndromecancer syndrome

▪▪ Atypical proliferative Atypical proliferative benign breast disease/ benign breast disease/ family historyfamily history

▪▪ Any first degree relative with Any first degree relative with history of BChistory of BC

▪▪ High socioeconomic classHigh socioeconomic class

▪ ▪ Prolonged uninterrupted Prolonged uninterrupted menses (late first pregnancy, menses (late first pregnancy, nulliparous)nulliparous)

▪ ▪ Postmenopausal obesityPostmenopausal obesity

▪▪ Personal history of prior CA Personal history of prior CA of ovary/ endometriumof ovary/ endometrium

▪▪ Proliferative benign breast Proliferative benign breast disease, if no atypiadisease, if no atypia

▪ ▪ Moderate alcohol Moderate alcohol intakeintake

▪▪ Menarche <12 years Menarche <12 years oldold

▪ ▪ ? HRT? HRT

▪▪ ? Oral ? Oral contraceptivescontraceptives

▪ ▪ DietDiet

Histopathologic Subtypes

• Carcinoma Insitu (Cis)– Ductal carcinoma insitu (DCIS)– Lobular carcinoma insitu (LCIS)– Paegt`s Diease

• Invasive Cancer– Ductal– Lobular– Modularly– Papillary – Mucinous– Tubular

Inflammatory Carcinoma

IDC ILC

Tubular Mucinous Medullary

DCIS

This photomicrograph demonstrates strong positive nuclear staining for estrogen

receptor in an infiltrating ductal carcinoma

Immunoperoxidase stains assess protein overexpression by the presence of strong membrane

reactivity. This photomicrograph illustrates strong (3+) membrane positivity in an IDC.

Pathological and prognostic factors

Histological subtypes ( IDC = 85% = NOS),( ILC= 5-10%),.

Mucinous, Medullary, Tubular, Papillary

Nuclear and histological Grade

Estrogen and progesterone receptor status

HER-2 overexpression

Proliferation marker (s-phase fraction, Ki-67)

Aneuploidy / P53

LN +ve vs –ve numbers

LVI

Warning SignsWarning Signs Warning SignsWarning Signs

A Hard, Painless, Lump or Thickening.A Hard, Painless, Lump or Thickening.

Change In Breast Size, or Shape.Change In Breast Size, or Shape.

Nipple Pain or Retraction.Nipple Pain or Retraction.

Breast Skin Irritation or Dimpling.Breast Skin Irritation or Dimpling.

Nipple DischargeNipple Discharge(spontaneous, unilateral, or bloody)(spontaneous, unilateral, or bloody)

A Hard, Painless, Lump or Thickening.A Hard, Painless, Lump or Thickening.

Change In Breast Size, or Shape.Change In Breast Size, or Shape.

Nipple Pain or Retraction.Nipple Pain or Retraction.

Breast Skin Irritation or Dimpling.Breast Skin Irritation or Dimpling.

Nipple DischargeNipple Discharge(spontaneous, unilateral, or bloody)(spontaneous, unilateral, or bloody)

Grave Signs ?Grave Signs ? Grave Signs ?Grave Signs ?

Core biopsy / fine-needle aspiration.

Experienced breast-imaging radiologist for tissue sampling ( ultrasound or mammogram guidance).

Manual Expression of spontaneous nipple discharge (Cytopathology examination).

Ductal lavage with saline solution to obtain nipple aspirate fluid.

FNAC cannot differentiate between invasive and noninvasive cancer , and even sometimes difficult to differentiate between Benign /Malignant lesion alone.

Request special studies for ER/PR (IHC) and, possibly, for HER2 over expression (FISH or IHC) if histopathology confirms invasive breast cancer.

Core biopsy / fine-needle aspiration.

Experienced breast-imaging radiologist for tissue sampling ( ultrasound or mammogram guidance).

Manual Expression of spontaneous nipple discharge (Cytopathology examination).

Ductal lavage with saline solution to obtain nipple aspirate fluid.

FNAC cannot differentiate between invasive and noninvasive cancer , and even sometimes difficult to differentiate between Benign /Malignant lesion alone.

Request special studies for ER/PR (IHC) and, possibly, for HER2 over expression (FISH or IHC) if histopathology confirms invasive breast cancer.

BIOPSYBIOPSY

Management of palpable breast mass

Clinical breast examination by primary provider.

If pt is under 30 and mass feels benign ultrasound may be sufficient to verify cyst.

If mass is cystic, it can be aspirated with follow up in 3-4 months.

If pt is over 30, ultrasound and diagnostic mammogram are indicated.

If mass is solid, FNA or core needle biopsy.

If initial biopsy is negative, excisional biopsy mass be warranted.

WHAT TO DO NOW AFTER DIAGNOSIS WHAT TO DO NOW AFTER DIAGNOSIS WHAT TO DO NOW AFTER DIAGNOSIS WHAT TO DO NOW AFTER DIAGNOSIS

??

•Physical Examination

•Mammogram +/- US

•Core biopsy (Tue Cut)

Triple assessment

Diagnosis

•Bloods (CBC, LFTs, Bone profile, Markers, U & Es)

•Echo &/or Muga Scan

•CT CAP

•Bone Scan

Pretreatment workup

Staging & Fitness

What further imaging tests are required?

• DCIS or pathological Stage I–routine bone scan, liver ultrasound and CXR

are not indicated as part of baseline staging.’

%of pts with test result

CXR 0.1%

Liver U/S 0%

Bone scan 0.5%

Cancer Care Ontario Practice Guidelines, CMAJ 164, 1439-1444, 2001.

What further imaging tests are required?

•Pathological Stage II–Bone scan–…‘routine liver ultrasound and CXR are not

indicated …but could be considered for patients with 4 positive nodes.’ OR Close margine < 2m

%of pts with test result

CXR ~0.2%

Liver U/S ~0.4%

Bone scan ~2.4%

Cancer Care Ontario Practice Guidelines, CMAJ 164, 1439-1444, 2001.

STAGINGSTAGING

Stage Stage 0 0

cancer breastcancer breast

Stage Stage 0 0

cancer breastcancer breast

DCISDCIS

(± LCIS)(± LCIS)LCISLCIS Paget’sPaget’s

Breast Cancer Continuum: Breast Cancer Continuum: intervention possibilitiesintervention possibilitiesBreast Cancer Continuum: Breast Cancer Continuum: intervention possibilitiesintervention possibilities

Prevention of ClinicallyDetectable Breast Cancer

Pre- Malignant Conditions

LCIS

Women at Increased Risk

Women at Increased Risk

Non- Invasive Cancer

DCIS

Prevention of Contralateral Breast Cancer 3.2%

Tumors< 1cm

Early Stage

node -ve

Early Stage

node +ve

Prevention of RecurrencePrevention of Recurrence

Late StageCancer

Late StageCancer

Recurrenceof BreastCancer

Recurrenceof BreastCancer

Prevention of Progression

Prevention of Progression

SURVIVALSURVIVAL

STAGESTAGE SURVIVAL RATE %SURVIVAL RATE %

II 96%96%

IIII 82%82%

IIIIII 53%53%

IVIV 18%18%

LOCO-REGIONAL CONTROL

LOCO-REGIONAL CONTROL

Surgery +RadiotherapySurgery +Radiotherapy

Treatment of early Breast CancerTreatment of early Breast Cancer

SYSTEMIC CONTROLSYSTEMIC CONTROL

Chemotherapy + HormonalNew Modalities

Chemotherapy + HormonalNew Modalities

What treatment would you What treatment would you recommend?recommend?

““For patients with stage I or II breast cancer, For patients with stage I or II breast cancer, BCS followed by radiotherapy is generally BCS followed by radiotherapy is generally recommended. In the absence of special recommended. In the absence of special reasons for selecting mastectomy, the choice reasons for selecting mastectomy, the choice between BCS and mastectomy can be made between BCS and mastectomy can be made according to the patient’s circumstances and …according to the patient’s circumstances and …preferences.”preferences.”

Canadian consensus document. CMAJ 158(Suppl 3), 1998

What treatment would you recommend?What treatment would you recommend?

Advantages of BCT

• Cosmetic• Psychological

Disadvantages of BCT

• Time• Convenience• Late toxicity

*Major criteria for BCT,negative margin , mammography is also important

Stage I – II breast cancerStage I – II breast cancer

Outcome after BCS + RT Mastectomy• Survival

DFS

Distant metastases

Loco-Regional Control (except EORTC)

No Disadvantage in the use of BCS in Axillary N+ pt.

No different in the rate of ….breast or control ……

See next

Mastectomy vs BCTMastectomy vs BCT

• NCI (Milan) trial • NSABP B-06 trial • NCI(France) trial • NCI (USA) trial • Danish Group trial • Metaanalysis Morris et al • Metaanalysis EBCTCG

All shows no difference in OS , DFS , Distance mets., Except EORTC is the only trial whaich showed significant difference in

loco-regional recurrence at 10 years 20% vs 12 in favor of mastectomy

Reasons for Choosing MastectomyReasons for Choosing Mastectomy(Contraindications to Radiotherapy)(Contraindications to Radiotherapy)

• patient preference

• physical / psychological inability to tolerate radiotherapy

Reasons for Choosing MastectomyReasons for Choosing Mastectomy

(Contraindications to Radiotherapy(Contraindications to Radiotherapy) ) – 2– 2

High risk of recurrence

• Multicentric disease 2 primary tumors in separate quadrants

• Diffuse malignant calcifications

• Persistant positive margins

• Locally advanced disease (most T3, T4)

Reasons for Choosing MastectomyReasons for Choosing Mastectomy

(Contraindications to Radiotherapy(Contraindications to Radiotherapy) ) – 3– 3

Contraindications to radiotherapy

• Pregnancy• Scleroderma or active SLE• Previous breast radiotherapy (e.g. mantle RT)

Cosmetic

• Large tumor in small breast

Absolute ContraindicationsAbsolute Contraindications

1. Multicentric disease 2 primary tumors in separate quadrants

2. Diffuse malignant calcifications

3. Persistant positive margins

4. Locally advanced disease (most T3, T4)

5. Pregnancy

Relative ContraindicationsRelative Contraindications

• Hist. Of collage / vascular Disase – Scleroderma or active SLE

• Multiple gross tumors in the same quarant + intermediate calcification

• Large tumor in small breast (significant cosmetic alteration )

Factors which are Factors which are NOTNOT contraindications contraindications to BCS + RTto BCS + RT

• Age• Histology • Central tumor• Paget’s disease of nipple• LCIS, DCIS, EIC (if clear margins)

• Breast implants• N+ disease• High risk of distant metastases• Strong family history • BRCA 1 / 2 +(hearedatery breast ca)• Presence of comorbid condition

Factors affecting Radiotherapy Factors affecting Radiotherapy Treatment DecisionsTreatment Decisions

• Patient fit for treatment?

• Multicentric disease?

• Diffuse malignant calcifications?

• Tumor size, stage

• Nodal status

• Margins

MarginsMargins• Margins status remain one of the most important independent

factor involved with long term local recurrence .

Risk of local recurrence (5y) with xrt is approximately : 5% in negative

10% in focally+

20% in diffusely+.

Indications for Re-excisionIndications for Re-excision

1. Positive margina) Invasive tumor cells at marginb) DCIS at marginc) EIC with positive margin

2. Unknown margin

3. Inadequate excision by specimen mammography

4. Focally positive**But…focally positive margin ( 3 LPF) or close margin can be treated with many Rx. Option :1. Re-exceision2. Radiotherapy boost3. Chemotherapy

Is radiotherapy necessaryIs radiotherapy necessary ? ? (given small tumor size and clear margins ) (given small tumor size and clear margins )

• “Women who undergo BCS should be advised to have postoperative breast irradiation”

Canadian consensus document. CMAJ 158(Suppl 3), 1998

Randomized Trials of Randomized Trials of BCS vs. BCS + BCS vs. BCS + RTRT

n Local Recurrence Rate (%)

BCS BCS+RT

NSABP 1265 15 yr 36 12

OCOG 837 10 yr 40 18

See Table 2


• Age > 50• Tumor 1 cm• Clear margins ( 2 mm )• N0

• Mucinous or tubular histology

Low Risk for IBTR after Breast Conserving Surgery alone

…but


In randomized trials of BCS + RT,

all subgroups appeared to benefit from RT

INDICATIONS FOR ADJUVANT RADIOTHERAPY INDICATIONS FOR ADJUVANT RADIOTHERAPY TO THE BREASTTO THE BREAST

• Indications for Breast Adjuvant Radiotherapy post Lumpectomy?

All cases.

No subset has been found for which radiotherapy does not reduce local recurrence significantly.

• Indications for Chest Wall Adjuvant Radiotherapy?T3 especially if other risk factors present (2-3 lymph nodes, high grade, very large, etc.)T4

4 or more axillary lymph nodes +

Systemic TherapySystemic Therapy

ChemotherapyChemotherapyHormonal TherapyHormonal TherapyTargeted TherapyTargeted Therapy

ChemotherapyChemotherapy

NeoadjuvantNeoadjuvantAdjuvantAdjuvantPalliativePalliative

Why Chemotherapy ? Why Chemotherapy ?

EBCTCG summarized results of 47 trials comparing chemotherapy

and no chemotherapy .

A significant reduction in mortality was seen in pts receiving

chemotherapy regardless of nodal status, and use of Tamoxifen.

Benefit of chemotherapy does vary with pt age and menopausal

status.

Women under age of 50 derive a greater survival benefit.

Tumor with higher “recurrence scores” may derive much greater

benefit whereas “low recurrence rate” tumors may derive little or no

benefit.

EBCTCG summarized results of 47 trials comparing chemotherapy

and no chemotherapy .

A significant reduction in mortality was seen in pts receiving

chemotherapy regardless of nodal status, and use of Tamoxifen.

Benefit of chemotherapy does vary with pt age and menopausal

status.

Women under age of 50 derive a greater survival benefit.

Tumor with higher “recurrence scores” may derive much greater

benefit whereas “low recurrence rate” tumors may derive little or no

benefit.

meta-analysis by the (EBCTCG)

Bonadonna et al.1995: : the results of 20 years of follow-up

Chemotherapeutic agents In Metastatic Disease

Docetaxel Paclitaxol Vinorelbine Capecitabine Gemcitabine Liposomal doxorubicin Abraxane Epirubicin Irinotecan Cyclophosphamide 5FU

- Debate exists over whether maximum tumor reduction through combination chemotherapy leads to prolonged survival.

- Usage of sequential single agent s to minimize side effects and preserve quality of life.

Best regimen still (unknown) Node negative Node negative Node positiveNode positive

AC x 4 or 6 AC x 4 →Taxol x4

FAC or CAF x 6 TAC

FEC or CEF x 6 AC x 4 → Taxol/Herceptin

C MF FAC or FEC x 6

A/E →CMF

A → T → C

Retrospective evidence suggests that doxorubicin-based chemotherapy regimens may be superior to non-doxorubicin-based

regimens in patients with tumors over-expressing HER-2 by IHC. Am J Clin Oncol 1989; 12; 123-128

Retrospective evidence suggests that doxorubicin-based chemotherapy regimens may be superior to non-doxorubicin-based

regimens in patients with tumors over-expressing HER-2 by IHC. Am J Clin Oncol 1989; 12; 123-128

For node-positive patients, anthracycline-containing chemotherapy regimens are preferred.

J Clin Oncol 20:2812-2823, 2002

Nausea and vomitingNausea and vomiting Hair lossHair loss Weight controlWeight control DiarrheaDiarrhea ConstipationConstipation Low blood countsLow blood counts Taste changesTaste changes Mouth soresMouth sores Premature menopausePremature menopause

How should How should radiotherapy and radiotherapy and chemotherapy be chemotherapy be combined?combined?

How should radiotherapy and chemotherapy How should radiotherapy and chemotherapy be combined?be combined?

Sequential Sequential RTRT CT CT SequentialSequential CT CT RT RT ““Sandwich”Sandwich” CT CT RT RT CT CT ConcurrentConcurrent


““Sandwich”Sandwich” CT CT RT RT CT CT ConcurrentConcurrent CT + RTCT + RT

Increased acute and late Increased acute and late toxicity,especially with concurrent toxicity,especially with concurrent treatmenttreatment

Cosmetic result probably inferiorCosmetic result probably inferior


Sequential Sequential RTRT CT CT SequentialSequential CT CT RT RT

? Delay in RT ? Delay in RT local local recurrencerecurrence

? Delay in CT ? Delay in CT distant metsdistant mets

How should radiotherapy and chemotherapy be How should radiotherapy and chemotherapy be combined?combined?

Dana Farber Study of SequencingDana Farber Study of Sequencing

244 Stage I,II244 Stage I,II CT CT RT vs RT RT vs RT CT CT

Early results showedEarly results showed– CT first arm CT first arm local recurrencelocal recurrence– RT first arm RT first arm distant failuredistant failure

ASTRO 2001 updateASTRO 2001 update: : at 11 yrs median F/U; at 11 yrs median F/U; no difference in TTF, time to DM, OS, local no difference in TTF, time to DM, OS, local recurrencerecurrence

Additional studies requiredAdditional studies required

Hormonal Therapy

NeoadjuvantAdjuvantPalliative

Endocrine Therapy: Approaches

• Estrogen receptor modulators– Tamoxifen (selective estrogen-receptor

modulator, or SERM)– Toremifene– Raloxifene

• Sex steroids• Aromatase inhibitors

– Nonselective AIs– Selective AIs

• pure anti-estrogens• ovarian ablation or suppression

– Medical– Surgical– Radiotherapy

Mechanism of Hormonal TherapyMechanism of Hormonal Therapy

LHRH(hypothalamus)

LHRH(hypothalamus) Pre/post-

menopausalPre/post-

menopausal

Premenopausal Premenopausal

(ACTH)(ACTH)

AdrenalglandsAdrenalglands

Pituitary glandPituitary gland

OestrogensProgesteroneOestrogens

Progesterone

ProgesteroneProgesterone

Androgens OestrogensAndrogens Oestrogens

Peripheral conversionPeripheral conversion

OvaryOvary

LHRH analogue Down- Regulation of HRH R

LHRH analogue Down- Regulation of HRH R

(FSH + LH) (FSH + LH)

TAMOXIFENTAMOXIFEN

AROMATASEInhibitor

AROMATASEInhibitor

Definition/Criteria of MenopauseDefinition/Criteria of Menopause

Profound and permanent decrease in ovarian estrogen synthesis.

Criteria for menopause include:

- Prior bilateral oophorectomy

- Age 60 y

- Amenorrheic for ≥12 months (In the absence of

chemotherapy, tamoxifen, Toremifene, or ovarian suppression

and FSH and Estradiol in the postmenopausal range).

- If taking Tamoxifen or Toremifene, and age < 60 y, then FSH and plasma Estradiol level in postmenopausal ranges.

In women premenopausal at the time of adjuvant chemotherapy, amenorrhea is not a reliable indicator of menopausal status.

Mechanism of action of Tamoxifenas an antitumour agent

Antioestrogen effects - blockage of oestrogen

receptor

STROMALCELL

STROMALCELL

Local effects - independent of oestrogen receptor

Local effects - independent of oestrogen receptor

+

-

INCREASE TGF-βINCREASE TGF-β

DECREASE TGF- TGF-ααDECREASE TGF- TGF-αα

The inhibition of oestrogen-stimulated growth in BC by The inhibition of oestrogen-stimulated growth in BC by TAMOXIFENTAMOXIFEN

ER→ER-TAMER→ER-TAM

TAMOXIFENTAMOXIFEN

AutocrineGrowth Factors

AutocrineGrowth Factors

TGF-TGF-IGF-1IGF-1

Plasminogen -ActivatorPlasminogen -Activator

TGF-TGF-

STIMULATESSTIMULATES

INHIBITSINHIBITS

INHIBITSINHIBITS

GROWTHARRESTGROWTHARREST

Sites of peripheral aromatisation

BreastTumourBreast

TumourMuscleMuscle FatFat LiverLiver

Figure AHypersecretion of LH following acute

administration of LHRH analogue

PituitaryPituitaryCellCell

PituitaryPituitaryCellCell LHLHLHLH

Figure BHyposecretion of LH following chronic

administration of LHRH analogue

LHLHLHLH

Mechanism of action of LHRH analogueMechanism of action of LHRH analogue



Targeted

Therapy

Targeted

Therapy

Promising agents in researchPromising agents in research

– EGFREGFR– Anti angiogenesisAnti angiogenesis– Vascular targetingVascular targeting– Gene therapyGene therapy

Promising agents in researchPromising agents in research

– EGFREGFR– Anti angiogenesisAnti angiogenesis– Vascular targetingVascular targeting– Gene therapyGene therapy

Therapeutic intervention at key stagesTherapeutic intervention at key stages in tumour development in tumour development

Epidermal Growth Factor Receptor (EGFR)

Breast 14 % - 91 %

Colon 25 % - 77 %

NSCLC 40 % - 80 %

Ovarian 35 % - 70 %

Pancreatic 30 % - 50 %

Head & Neck 80 % - 95 %

EGFR Expression Rate

TumourTumour

Targeted Therapy

Trastuzumab Trastuzumab (Herceptin)(Herceptin)

Bevacizumab (Avastin) (Avastin) Lapatinib (taykreb) Erlotinib (Tarceva)

MonthsMonths

0.2

0

0.4

0.6

0.8

1.0

FISH+

Months

0.2

0

0.4

0.6

0.8

1.0 Trast. + CT (n = 176)

CT (n = 169)

Pro

bab

ility

of

surv

ival

RR = 0.71p = 0.007

0 10 20 30 40 50

20.0 mo

26.2 mo

FISH–

RR = 1.11p = NS

0 10 20 30 40 50

19.8 mo24.0 mo

Trast. + CT (n = 50)

CT (n = 56)

Herceptin Combination Pivotal Trial: Overall Survival

Update of Mass. Proc Am Soc Clin Oncol. 2001;20:22a. Abstract 85.EM, RMH 30.11.2006

8.5 months

Time (months)

Extra et al.ASCO 2005; abs 555

Docetaxel ± Herceptin trial (M77001)

1.00.90.80.70.60.50.40.3

0.20.1

0.0

0 5 10 15 20 25 30 35 40 45 50

Herceptin + docetaxelDocetaxel

+37%

22.7 31.2

Documented crossover 57%

Probabilityof survival

EM, RMH 30.11.2006

100100

8080

6060

4040

2020

00

PatientsPatients

(%)(%)

Months from randomisationMonths from randomisation66 1122 1188 2244

16931693 11108108 767767 445445 22242416941694 11117272 885885 532532 268268

127127

220220

1-year Herceptin1-year Herceptin

ObservationObservation

00

No. No. at risk at risk

EventsEvents HRHR 95% CI95% CI p valuep value

0.540.54 0.43, 0.670.43, 0.67 <0.001<0.001

2-year2-yearDFSDFS

85.885.8

77.477.4

HERA DFS

Median follow-up: 1 yearMedian follow-up: 1 yearHR, hazard ratio; CI, confidence intervalHR, hazard ratio; CI, confidence interval

EM, RMH 30.11.2006

B31 / N9831 combined analysis Overall survival

94%94%91%91%

87%87%92%92%

0 1 2 3 4 550

60

70

80

90

100

Years from randomisation

HR=0.67; p=0.015

Deathsn6292

16721679

Patients Patients (%)(%)

ACPHACP

Romond et al 2005EM, RMH 30.11.2006

Nutritional Guidelines Nutritional Guidelines

Eat a variety of healthful foods, with an Eat a variety of healthful foods, with an emphasis on plant sources.emphasis on plant sources.

Adopt a physically active lifestyle.Adopt a physically active lifestyle.

Maintain a healthful weight throughout Maintain a healthful weight throughout life.life.

No alcoholic beverages.No alcoholic beverages.

Eat a variety of healthful foods, with an Eat a variety of healthful foods, with an emphasis on plant sources.emphasis on plant sources.

Adopt a physically active lifestyle.Adopt a physically active lifestyle.

Maintain a healthful weight throughout Maintain a healthful weight throughout life.life.

No alcoholic beverages.No alcoholic beverages.

Case 1Case 1

34 yr. 34 yr. oold, premenld, premenopausalopausal female female with upper outer quadrant mass with upper outer quadrant mass in left breast. Mammogram in left breast. Mammogram shows a 2 cm. spiculated nodule shows a 2 cm. spiculated nodule and core biopsy is positive for and core biopsy is positive for carcinoma. She is referred prior carcinoma. She is referred prior to surgery for a discussion of to surgery for a discussion of treatment options for the breast.treatment options for the breast.

Case 2Case 265 yr. 65 yr. oold, postmenld, postmenopausalopausal female with upper female with upper outer quadrant mass in left breastouter quadrant mass in left breast, undergoes , undergoes wide local excision and axillary node dissection. wide local excision and axillary node dissection. She is otherwise in good health. She is otherwise in good health.

Pathology: Pathology: – invasive lobular carcinoma, 2.5 x 2.1 x 1.8 invasive lobular carcinoma, 2.5 x 2.1 x 1.8

cm;cm;– Bloom- Richardson grade 2 (SBR 6/9)Bloom- Richardson grade 2 (SBR 6/9)– ERER+ + PRPR++– lymphovascular invasion presentlymphovascular invasion present– Margins clear by 1 mm. or moreMargins clear by 1 mm. or more– 2 lymph nodes contain metastases (of 10 2 lymph nodes contain metastases (of 10

resected nodes) with microscopic extranodal resected nodes) with microscopic extranodal extensionextension

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HIGHLIGHTS ON BREAST CANCER Eyad Alsaeed MD, FRCPC. Consultant Radiation Oncologist Acting Chairman...

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