Common Lecture on Breast Cancer

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ONCOLOGIC MANAGEMENT OF BREAST CANCER

OBJECTIVESTo answer the questions frequently asked by our colleagues regarding systemic therapy and radiotherapy in breast cancer

Expectations of an oncologist from surgeons and pathologists in breast cancer

QUESTIONSWhat are the indications of chemotherapy and radiotherapy in early breast cancer?What is hormone therapy? Should tamoxifen be given to all patients?What is neoadjuvant and adjuvant therapy. Indications of chemotherapy/radiation therapy before and/or after surgery in locally advanced breast cancer?In which patients no systemic/radiation therapy should be given?

QUESTIONS

Is axillary radiation as effective as axillary lymph node dissection?What is immunotherapy? What is Her-2 neu and Herceptin?What specific parameters are assessed while planning chemo/radiotherapy?What is the role of chemotherapy/hormone therapy in cases of LCIS/DCIS?In inflammatory carcinoma breast, is pre-op chemotherapy/radiotherapy indicated?

TERMINOLOGIESNeoadjuvant therapyTreatment given prior to the primary treatment in order to make the tumor amenable to primary treatment (usually surgery or radiation)Adjuvant therapyAdditional therapy given for the possibility of subclinical and subradiological metastasis that would not otherwise be treated by the primary treatment modalitySalvage therapyAfter failure of other treatments (surgery, radiation or chemotherapy), salvage treatment is used to control disease or provide palliationHormonal therapyTherapy to induce response in a tumor by altering the hormonal environment

TERMINOLOGIESDuctal carcinoma in situ DCISMalignant cells are confined to the lumen of the duct and do not breach the basement membraneLobular carcinoma in situ LCISMalignant cells are confined to the lumen of the lobule and do not breach the basement membraneInvasive ductal carcinomaMalignant cells arising from the duct system breach the basement membraneInvasive lobular carcinomaMalignant cells arising from the lobules breach the basement membraneInflammatory Carcinomacharacterized by diffuse brawny induration of the skin with an erysipeloid edge, usually with no underlying mass.

GLOBAL ISSUE

BREAST CANCER INCIDENCE & MORTALITYaaaaaaaaa

PAKISTANI STATISTICSTOP MALIGNANCY SEEN AT SKMH&RC AMONG ALL AGE GROUPS & BOTH SEXES COMBINED FROM DEC 1994 TO DEC 2004TOP MALIGNANCY SEEN AT SKMH&RC AMONG FEMALES ALL AGE GROUPS COMBINED FROM DEC 1994 TO DEC 2004

Hameed S, etal, http://www.shaukatkhanum.org.pk/pdf/Cancer%20Registry%20Report%20-1994-2004_10%20years_.pdf

Count%age of totalBreast511921.26%

Count%age of totalBreast506042.37%

BREAST CANCER DEMOGRAPHICSAnderson WF et al. Breast Cancer Res Treat 2002; 76: 273624.956.935.7 64.3 41.4 50.1 8.5

75.163.320.1 79.9 28.8 65.1 6.1ER-positiveER-negativeProportion of patients (%)Mean age (years)Age at diagnosis (%) 2.0 cm 2.0 cm unknownPatients (n=82,488)ER = oestrogen receptor

RISK FACTORSEstablished Risk Factors

Risk factorCategory at riskOlder age Older than 50Country of residenceNorth America or northern EuropeGerm-line mutation With BRCA1 or BRCA2 mutationsPersonal history of breast cancer With history of invasive breast carcinomaHigh radiation exposure to chest area With high radiation exposure to chestAtypical hyperplasia in breast biopsy With atypical hyperplasiaCytological findings (fine-needle aspiration; nipple aspiration fluid Proliferation with atypia

RISK FACTORSEstablished Risk Factors

Risk factorCategory at riskFamily history of breast cancer With one or more close relatives with breast cancerEarly menarcheMenarche before age 12Late menopauseMenopause after age 55Older age at first full-term birthOlder than 30 years when first child was bornUsing menopausal hormone therapyWith hormone treatment after menopauseObesity after menopauseObese after menopause

RISK FACTORSOther reported risk factors

Risk factorCategory at riskUsing birth control pillsCurrent useTall heightTaller than 5 ft 9 inchesRegular alcohol consumptionRegularly consume alcoholic beveragesBreast-feedingNonePostmenopausal body mass index (BMI)Higher BMIJewish heritageYes

RISK FACTORSPossible risk

Risk factorCategory at riskHigh-density breasts on mammogramsWith high-density mammogramsHigh socioeconomic positionHave high socioeconomic positionPhysical activityLowerDietary factorsHigh-fat, low-fiber diet

WHO SHOULD BE OFFERED GENETIC TESTING (BRCA1 & BRCA2 MUTATIONS)ASCO RecommendationsThe individual has personal or family history features suggestive of a genetic cancer susceptibility condition,

The test can be adequately interpreted, and

The results will aid in diagnosis or influence the medical or surgical management of the patient or family members at hereditary risk of cancer

BREAST CANCER SCREENING

Age GroupACRACSNCI2039BSE optional; CBE every 3 years.Monthly BSE; CBE every 3 years.No recommendation.4049Annual mammography and CBE from 40 years.Annual mammography and CBE from 40 years.Mammography every 12 years.>49Annual mammography and CBE as long as a woman is in reasonably good health.Annual mammography and monthly CBE as long as a woman is in reasonably good health.Mammography every 12 years.

BREAST CANCER SCREENING

Age GroupACRACSNCIAt increased riskConsult with their doctors about the benefits and limitations of starting mammography screening earlier, having additional tests (i.e., breast ultrasound and MRI), or having more frequent examinations.Consult with their physician about beginning mammography screening before age 40.Seek expert medical advice about whether they should begin screening before age 40 and the frequency of screening.

SYMPTOMS

Painless Breast Mass65%Painful Breast Mass12%Nipple Discharge7%Skin Dimpling4%Nipple Retraction3%Local Edema3%

DIAGNOSIS

DIAGNOSTIC WORKUPGeneralHistory with emphasis on presenting symptoms, menstrual status, parity, family history of cancer, other risk factorsPhysical examination with emphasis on breast, axilla, supraclavicular area, abdomen Special testsBiopsy (core biopsy directed by physical examination, ultrasound, or mammography as indicated, or needle localization) Radiologic studiesBefore biopsyMammography/ultrasonographyChest radiographsMagnetic resonance imaging of breast (selected cases)

DIAGNOSTIC WORKUPRadiological studiesAfter positive biopsyBone scan (when clinically indicated, for stage II or III disease or elevated serum alkaline phosphatase levels)Computed tomography of chest, abdomen and pelvis for stage II or III disease and/or abnormal liver function tests Laboratory studies Complete blood cell count, blood chemistryUrinalysisOther studiesHormone receptor status (ER, PR)HER2/neu statusConsider genetic counseling/BRCA testing in selected cases

DIAGNOSTIC ACCURACY OF VARIOUS MODALITIES

TestSensitivitySpecificityCBE60-89 %60-99 %Mammography83-93 %73-97 %Ultrasound89-91 %97-98 %FNAC65-98 %93-99 %Combined99-100 %99-100 %

AJCC AND UICC CANCER STAGING SYSTEM

TxPrimary tumor cannot be assessedToNo evidence of primary tumorTisCarcinoma in situTis(DCIS)Ductal carcinoma in situTis(LCIS)Lobular carcinoma in situTis PagetsPagets disease of nipple with no tumorT1Tumor 2cm in greatest dimensionT1micMicroinvasion 0.1cm or less in greatest dimensionT1aTumor >0.1cm but not >0.5cm in greatest dimensionT1bTumor >0.5cm but not >1cm in greatest dimensionT1cTumor >1cm but not >2cm in greatest dimension

T2Tumor >2cm but not >5cm in greatest dimensionT3Tumor >5cm un greatest dimensionT4Tumor of any size with direct extension to skin or chest wall, only as described belowT4aExtension to chest wall not including pectoralis muscleT4bEdema including peau de orange or ulceration or satellite skin nodules confined to same breastT4cBoth T4a and T4bT4dInflammatory carcinoma

STAGING SYSTEM

NxRegional lymph nodes cannot be assessedNoNo regional lymph node metastasisN1Metastasis to movable ipsilateral axillary lymph node(s)N2aMetastasis to ipsilateral matted axillary lymph node(s) or fixed to other structures N2bMetastasis in clinically apparent ipsilateral internal mammary lymph nodes in absence of clinically evident ipsilateral axillary lymph node metastasisN3aMetastasis in ipsilateral infraclavicular lymph node(s)N3bMetastasis in ipsilateral internal mammary lymph node(s) and axillary lymph node(s)N3cMetastasis in ipsilateral supraclavicular lymph node(s)

STAGING SYSTEM

pNoNo regional lymph node metastasispN1Metastasis to 1 to 3 positive axillary lymph node(s)pN2Metastasis to 4 to 9 positive axillary lymph nodespN3Metastasis to 10 or more positive axillary lymph nodes

MxDistant metastasis cannot be assessedMoNo distant metastasisM1Distant metastasis

StageTumor (T)Node (N)Metastasis (M)Stage 0TisN0M0Stage 1T1N0M0Stage IIAT0N1M0T1N1M0T2N0M0Stage IIBT2N1M0T3N0M0Stage IIIAT0N2M0T1N2M0T2N2M0T3N1, N2M0Stage IIIBT4any NM0any TN3M0Stage IVany Tany NM1

CLINICAL STAGING OF BREAST CANCERStage IVStage IIIStage IIStage IMetastatic Localized (early) diseaseLocally advanced disease

AJCC HISTOPATHOLOGIC CLASSIFICATIONIn situ carcinomas NOS Intraductal (in situ) Paget's disease and intraductal Invasive carcinomas NOS Ductal Inflammatory Medullary, NOS Medullary with lymphoid stroma Mucinous Papillary (predominantly micropapillary pattern) Tubular Lobular Paget's disease Undifferentiated Squamous cell Adenoid cystic Cribriform

INFILTRATING DUCTAL CARCINOMA70% to 75% of all breast cancers (most common type)Arises from the milk ductsStony hard on palpationCommonly spreads to the lymph nodes = poor prognosis

5% to 10% of all breast cancers Arises from the lobules of the breast Tendency toward multicentric & bilateral involvement Generally poor prognosisINFILTRATING LOBULAR CARCINOMA

INFLAMMATORY CARCINOMA

1% and 4% of all breast cancers Characterized by red (inflamed) breast skin - pitted appearance looks like an orange peel (peau d'orange) Symptoms may mimic a mastitis, without fever or signs of infection. Generally associated with a poor prognosis. Long-term remission possible with aggressive treatment

PAGET'S DISEASE OF THE NIPPLE

3% of all breast cancersUnique type of ductal cancerCharacterized by a rash, itching, scaliness or redness on the nipple and an underlying ductal carcinomaFrequently noninvasive

SPECIAL TYPESMedullary cancer - good prognosisTubular breast cancers slow growing; small ones rarely involve the lymph nodes

Mucinous (or colloid) breast cancer - characterized by mucin around the tumor cells. The more mucinous the tumor, the more slow growing it is

PROGNOSTIC FACTORS FOR SURVIVAL AND METASTASIS

TUMOR SIZE

AXILLARY NODAL STATUS

TUMOR TYPEFavourable prognosis : Tubular, mucinous, medullary, papillary subtypes compared to invasive ductal or lobular carcinoma

Poor prognosis : Metaplastic, Undifferentiated subtypes

TUMOR GRADENottingham prognostic gradeBased on percentage of tubule formation, degree of nuclear pleomorphism, accurate mitotic countGrade I better survivalGrade II & III worse survival

ESTROGEN AND PROGESTERONE HORMONAL RECEPTORS IN TUMOR CELLS

LYMPHATIC AND VASCULAR INVASION Increase risk of recurrence

ESTROGEN AND PROGESTERONE HORMONAL RECEPTORS IN TUMOR CELLS

HER-2/neuHER-2/neu proto-oncogene (also called c-erbB-2) located on chromosome 17 codes for a transmembrane glycoprotein has tyrosine kinase activity

Amplified or overexpressed in up to 30% of in human breast carcinoma Overexpression of the protein is associated with tumor aggressiveness and decreased disease-free survival in node-positive patients, with variable prognostic significance among node-negative patients

AGEAlthough clearly not as valid as tumor size and nodal status, young age may be considered in combination with other prognostic factors in clinical decision making as a potential negative prognostic factor

OBESITY/BODY MASS INDEXOn multivariate analysis, recurrent disease developed in 32% of obese patients compared with 19% of nonobese women

SMOKINGThe RRs for smokers and exsmokers, compared with those who had never smoked, is 1.44 and 1.13

PREGNANCYNo strong evidence to suggest that subsequent pregnancy will increase the risk of recurrence

TUMOR LOCATION No sufficient evidence to support any independent prognostic significance of tumor location Medial tumor location may lead to the underestimation of axillary lymph node involvement

DUCTAL CARCINOMA IN SITU (DCIS)Stage 0, Tis No MoAverage age at diagnosis 54- 56 yrsPresenting signs/symptoms: mass, breast pain, bloody nipple dischargeMammography: microcalcificationsPathology: Less likely to be bilateral and approximately 30% incidence of multicentricity; Comedo and non-comedo variant. Comedo has higher proliferative rate, over expression of HER-2/neu and higher incidence of local recurrence and microinvasion.Risk of invasive cancer: 25-50 yrs within 10yrs of diagnosis. Virtually all are ductal, ipsilateral and generally in the same quadrant.DCIS considered direct precursor of invasive cancer.

MANAGEMENT OF DCIS

LOBULAR CARCINOMA IN SITU (LCIS)Stage 0 Tis No MoPeak age 45 50yrsNon palpableNo consistent mamographic features. Often incidental finding after biopsy performed for another reason.Pathology: multifocal, multicentric and bilateralRisk of invasive cancer 20 25% within 15yrs of diagnosis. Mostly ductal in origin with both breasts at riskLCIS considered a marker for risk of invasive cancer.Management options: Close follow up Chemoprevention trial Counselling regarding risk reduction with tamoxifen in premenopausal women or with tamoxifen or raloxifene for post menopausal women In special circumstances bilateral mastectomy reconstuction

MANAGEMENT OF INVASIVE DISEASE

SURGICAL MANAGEMENT BREAST CONSERVING SURGERY (BCS) For early breast cancerPartial mastectomy, lumpectomy/tylectomy, and quadrantectomyRe-excision under frozen section control in patients with +ive marginsRT may be used for focally +ive margins For diffuse involvement, dose of RT high increase toxicityLarge T2/T3 tumors neoadjuvant chemo followed by BCS

SKIN SPARING MASTECTOMY

NIPPLE SPARING MASTECTOMY

BCS is followed by RT Patient should be educated that mastectomy does not totally eliminate the need for RT in EBC

SURGICAL MANAGEMENT OF AXILLARY LYMPH NODES30-40% of breast cancer metastases to ALN 60-80 % of patients are lymph node negative Unnecessary surgery?Sentinel lymph node biopsy can spare the potential morbidity of ALND

SURGICAL MANAGEMENT OF AXILLARY LYMPH NODESAXILLARY LYMPH NODE DISSECTIONALND Clearance of level I and II axillary lymph nodes Minimum of 16 axillary lymph nodes need to be sampled to clearly follow current guidelines regarding RT to axilla and supraclavicular lymph nodes Sampling of ONLY clinically enlarged lymph nodes wrong practiceDistribution of Axillary lymph node involvement:Level I58%Level I & II22%Level I, II & III 16%Skip metastasis4%

SURGICAL MANAGEMENT OF AXILLARY LYMPH NODESSLNB - SLN is the first lymph node to receive lymphatic drainage from a tumor Axillary dissection if SLNB +ive Identification rate > 90 % False negative rate < 5 % Learning curve 30 - 50 cases (SLNB + ALND)

MASTECTOMY VS BCS

Study

No. Cases

Local Recurrence

(%)

Survival

(%)

FU

(Years)

MRM

BCS

MRM

BCS

NSABP

1219

8

10

59

63

12

Milan

701

4

7

65

65

18

NCI

237

6

16

75

77

10

EORTC

874

9

13

61

54

8

IGR

179

14

9

65

73

15

Danish

904

6

5

82

79

6

MASTECTOMY VS BCS

BREAST CONSERVING TREATMENT INDICATIONS Typically less than 5 cm lesion No multicentric disease Must have negative margins (>1mm) this includes DICS No scleroderma/ autoimmune disease Breast /tumor proportion cosmetic outcome

CONTRAINDICATIONSAbsolute Prior RT to the breast or chest wall RT during pregnancy (1st and 2nd trimester) Diffuse suspicious or malignant appearing microcalcifications Widespread disease that cannot be incorporated by local excision through a single incision that achieves negative margins with a satisfactory cosmetic result Positive pathologic margin

BREAST CONSERVING TREATMENTCONTRAINDICATIONS Relative Active connective tissue disease involving the skin (especially scleroderma and lupus) Tumors > 5 cm Focally positive margin Have an increased risk of ipsilateral breast recurrence or contralateral breast cancer with breast conserving therapy Prophylactic bilateral mastectomy for risk reduction may be considered Women 35 y or premenopausal women with a known BRCA 1/2 mutation

RT PRODUCES ITS GREATEST EFFECT ON LR IN WOMEN AT MOST RISKEBCTCG, Lancet (2005)366, 2087;Harris, Breast Cancer: Current Controversiesand New Horizons, July 12, 2007, Boston

5 Year LR BCS5 Year LRBCT+RT5 Year GainN-20.1%5.7%14.4%N+/Nx34%8.9%25.1%

ROLE OF RADIOTHERAPY FOR BREAST CANCERPalliativeLocal and metastatic disease control

INDICATIONS FOR ADJUVANT RADIOTHERAPY

Breast/Chest wall irradiationBreast Conserving Surgery > 2 positive axillary lymph nodesMatted lymph nodesTumor > 5cm. (T3, any T4)Extracapsular extensionPositive or close margins (less than 3 mm)Any skin, fascial or skeletal muscle involvementPoorly differentiated tumorsLymphatic permeation

INDICATIONS FOR ADJUVANT RADIOTHERAPY

Lymphatic irradiationFewer than 9 lymph nodes sampledTwo or more metastatic axillary lymph nodes Lymph nodes larger than 2.5cmInvolvement of apex of axillaGross extracapsular tumor extension

SURGICAL AXILLARY DISSECTION VS RT

SYSTEMIC THERAPYChemotherapyHormonal TherapyAdjuvant therapyNeoadjuvant therapyPalliative therapyBiologic Therapy

ST. GALEN CONSENSUS

Definition of Risk Categories for Patients with Operated Breast Cancer Low riskNode negative AND all of the following features: pT 2 cm, AND Grade 1, AND Absence of peritumoral vascular invasion, AND HER2/neu gene neither overexpressed nor amplified, AND Age 35 yearsIntermediate riskNode negative AND at least one of the following features: pT >2 cm, OR Grade 2-3,OR Presence of peritumoral vascular invasion,OR HER2/neu gene overexpressed or amplified,OR Age

ST. GALEN CONSENSUS

Definition of Risk Categories for Patients with Operated Breast Cancer High riskNode positive (13 involved nodes) AND HER2/neu gene overexpressed or amplified Node positive (4 or more involved nodes)

ST. GALEN CONSENSUSET Endocrine therapyCT - Chemotherapy

Expert Consensus on the Therapy of Breast Cancer Risk Category Endocrine Responsive Endocrine Response Uncertain Endocrine Nonresponsive Low riskETETNot ApplicableIntermediate riskET alone, orCT ET(CT + ET)CT ET(CT + ET)CTHigh riskCT ET(CT + ET)CT ET(CT + ET)CT

ST. GALEN CONSENSUS

BENEFIT OF ADJUVANT CHEMOTHERAPYDecreased recurrence rate ~ 20-40%Decreased mortality rate ~ 10-40%

DEVELOPMENT OF ADJUVANT CHEMOTHERAPY IN BREAST CANCER Before anthracyclinesCMF, CMFVPWith anthracyclinesCombinations: AC, FAC, AVCMF, FEC, CEFSequence and Alternating (Milan A & B)Dose intensity,dose density, HDCTTaxanes (Paclitaxel/Docetaxel)Sequential: A T C or AC T Combinations: TA, TACTargeted AgentsIntegration in chemotherapy strategies

1970s1980s1990s2000s

NEOADJUVANT / PRIMARY CHEMOTHERAPYAdvantages- Assessment of tumor response to chemotherapy- Prompt treatment of the micrometastases- May downstage the primary tumor- Increases the likelihood of BCSDisadvantages- Loss of prognostic information-ALN status- Delayed local or regional therapy- Induction of drug resistance

Core biopsy should always be performed prior to neoadjuvantchemotherapy to obtain sufficient tissue to identify histologic subtype,ER/PR status and Her2 Neu status

NEOADJUVANT / PRIMARY CHEMOTHERAPYIndications1. Locally advanced breast cancer - Stage IIIB, T4 or N3 cancer- Stage IIIA inoperable cancer2. T2 or T3 tumors, to make BCS feasible

NEOADJUVANT / PRIMARY CHEMOTHERAPYAdvantages- Assessment of tumor response to chemotherapy- Prompt treatment of the micrometastases- May downstage the primary tumor- Increases the likelihood of BCSDisadvantages- Loss of prognostic information-ALN status- Delayed local or regional therapy- Induction of drug resistance

Core biopsy should always be performed prior to neoadjuvantchemotherapy to obtain sufficient tissue to identify histologic subtype,ER/PR status and Her2 Neu status

ROLE OF HORMONAL THERAPYAdjuvant Hormonal TherapyPrimary Hormonal TherapyPalliative Hormonal TherapyPrevention of Breast Cancer

E2 = EstradiolER = Estrogen receptorE2ER = Estradiol-receptor complexPgR = Progesterone receptorHORMONE-DEPENDENT BREAST CARCINOMA

TYPE OF HORMONAL THERAPYGnRH-Agonists- Goserelin, LeuprolideAntiestrogens- Tamoxifen, Toremifen, Droloxifen, Faslodex, 3rd Generation SERMsAntiprogestins - Mifepristone, OnapristoneAromatase Inhibitors- Glutethimides, Steroidal AI - Letrozole (Femara), Anastrozole (Arimidex)

HORMONAL THERAPYTamoxifenAromataseInhibitors

AROMATASE INHIBITOR

HORMONAL THERAPYSince 1980 Tamoxifen has been the gold standard in first-line treatment of pre menopausal with breast cancer ER/PR +ve

The third generation aromatase inhibitors, letrozole and anastrozole first-line therapy in postmenopausal women

The selective aromatase inhibitors may prove to be the more effective/better tolerated drugs in the neo-adjuvant setting as well

Endocrine therapy is recommended for at least 5 years

PlaceboTamoxifenBREAST CANCER CONTINUUM: CONSISTENCY OF RESULTS ON 5 YEARS OF TAMOXIFEN

Improved Outlook in Early Breast Cancer:Indirect Comparison of ATAC data with EBCTCG 1995 Overview1(Hormone Receptor +ve Patients >50 Years)

HER FAMILY: RECEPTORS AND LIGANDSHER1HER2HER3HER4TyrosinekinasedomainLigandbindingdomainTransmembraneHerbst. Int J Radiat Oncol Biol Phys. 2004;59(suppl):21; Roskoski. Biochem Biophys Res Commun. 2004;319:1;Rowinsky. Annu Rev Med. 2004;55:433.

POTENTIAL CONSEQUENCES OF HER DYSREGULATIONSignaling cascadesHER familyPI3KMAPKNucleusPPAdapted from Roskoski. Biochem Biophys Res Commun. 2004;319:1-11; Rowinsky. Annu Rev Med. 2004;55:433-457.InvasionApoptosisProliferation

Normal (1X)~20,000-50,000 HER2 receptorsOverexpressed HER2 (10-100X)Up to ~2,000,000 HER2 receptorsExcessive cellular divisionHER2 OVEREXPRESSION IN BREAST CANCER

Pegram et al. Cancer Treat Res. 2000;103:57.Ross and Fletcher. Am J Clin Pathol. 1999;112(suppl 1):S53.Slamon et al. Science. 1987;235:177.HER2 is overexpressed in ~25% of breast cancers

Wolff et al. JCO 25: 118 (2007); nccn.orgHER2 TESTINGHER2 evaluation in all invasive breast cancer case at diagnosisLabs with greater experience have fewer false-positivesFISH and IHC are both appropriate testing methods when high concordance is establishedNew ASCO-CAP 2006 and NCCN Task force recommendations available: Guidelines for testingDefinitions of Pos\Neg\Intermediate resultsFISH retest of IHC 2+ Repeat FISH or perform IHC for FISH 1.8-2.2

ANTI-HER TARGETED APPROACHESAnti-EGFRblockingantibodies (eg, trastuzumab, cetuximab)Anti-ligandblockingantibodiesTyrosinekinaseinhibitors (eg, erlotinib, gefitinib, lapatinib)Ligand-toxinconjugates (eg, TP-38, DAB389EGF, scFv-14e1-ETA fusion toxin)HER dimerizationinhibitors (eg, pertuzumab)TOXINAdapted from Noonberg and Benz. Drugs. 2000;59:753.

TARGETING THE HER FAMILY: EXAMPLES OF THERAPIESMoAb = monoclonal antibody; TKI = tyrosine kinase inhibitor

AgentMechanism of ActionTargetMode of AdministrationTrastuzumabMoAbHER2IVCetuximabMoAbHER1IVPertuzumabMoAbHER1/HER2/HER3/HER4IVGefitinib, ErlotinibTKIHER1POLapatinibTKIHER1/HER2PO

SURVIVAL RATES5-year Survival by AgeYounger than 45Ages 45-64Ages 65 & older81% 85% 86%

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ST. GALEN CONSENSUS

ST. GALEN CONSENSUS

FIVE-YEAR SURVIVAL RATES(ACS Relative)http://www.cancer.org/docroot/CRI/content/CRI_2_4_3X_How_is_breast_cancer_staged_5.asp9/13/2007

Stage 0100%Stage I100%Stage IIA92%Stage IIB81%Stage IIA67%Stage IIIB54%Stage IV20%

***Breast cancer is highly curable if detected early, and since the majority of breast cancers are first noticed by the patient (as a lump in the breast), public and professional education may be the single most important factors in increasing the rate of early detection. Unfortunately, in developing countries, the majority of patientsoften as many as 80%, which is the inverse of the fraction in affluent nationshave advanced disease. Simply reducing the size of this problem would improve survival rates*A recent study obtained demographic data for more than 80,000 women with infiltrating ductal carcinoma and known oestrogen receptor (ER) status from the Surveillance, Epidemiology and End Results (SEER) database (Anderson et al, 2002). ER-positive disease was shown to be correlated with postmenopausal status and good prognostic factors (p 35 years of age) and at all levels of increased risk. The duration of the benefit continued for the duration of follow-up.

*1612*Herbst. Int J Radiat Oncol Biol Phys. 2004;59(suppl):21. Roskoski. Biochem Biophys Res Commun. 2004;319:1.Rowinsky. Annu Rev Med. 2004;55:433. *EGFR signaling is triggered by the binding of growth factors, such as epidermal growth factor (EGF), resulting in the dimerization of EGFR molecules or heterodimerization with other closely related receptors, such as HER2/neu. Autophosphorylation and transphosphorylation of the receptors through their tyrosine kinase domains leads to therecruitment of downstream effectors and the activation of proliferative and cell-survival signals.

Cell surface receptors bind ligands that activate the receptor and regulate cell functions.EGFR can bind EGF as well as several other ligands (eg, TGF).The binding of ligand results in 2 receptors joining together in a process known as dimerization.Upon dimerization, the intracellular tyrosine kinase domains of the receptor may transphosphorylate the dimer partner, initiating a signaling cascade. Subsequent transduction of the signal to the nucleus leads to regulation of genetic functions, such as gene activation/suppression and cell cycle regulation.

In malignancies, overexpression or dysregulation of EGFR may increase the signaling response and result inCell cycle progression leading to cellular proliferation.Decreased apoptotic response leading to increased cellular survival even in the presence of abnormal cell functions resulting from toxic stimuli such as radiation or chemical damage.Production of cell factors that promote angiogenesis and further cellular proliferation.Increased invasiveness and metastasis.

Roskoski R Jr. The ErbB/HER receptor protein-tyrosine kinases and cancer. Biochem Biophys Res Commun. 2004;319:1-11.Rowinsky EK. The erbB family: targets for therapeutic development against cancer and therapeutic strategies using monoclonal antibodies and tyrosine kinase inhibitors. Annu Rev Med. 2004;55:433-457.*In normal cells, HER2 mediates signaling for cell proliferation and survival.1When HER2 is overexpressed, the amount of HER2 protein on the cell surface increases 10- to 100-fold. This may lead to excessive cellular division and formation of tumors.2There can be as many as ~2,000,000 HER2 molecules per cell in malignant tissues, instead of the normal ~20,000-50,000 molecules per cell.3The presence of HER2 protein overexpression and gene amplification are highly correlated. The HER2 gene is amplified in about 25% of breast cancers.31. Rowinsky. Annu Rev Med. 2004;55:433.2. Slamon et al. Science. 1987;235:177.3. Pegram et al. Cancer Treat Res. 2000;103:57.*The ASCO and NCCN guidelines both recommend that HER2 status be determined for every case of primary invasive breast cancer at diagnosis to provide prognostic or predictive information.According to CAP guidelines, IHC and FISH are both appropriate testing methods for a local lab, provided that high concordance rates are established.>90% concordance for IHC 0/FISH and IHC 3+/FISH+Otherwise, both tests should be considered.Especially when FISH testing is unavailable in a local lab, IHC in that lab is recommended provided that high concordance is demonstrated and maintained.For all IHC 2+ cases, FISH validation is recommended.Experience has shown that labs with greater experience are more reliable than those that test infrequently (ie, they have fewer false-positives), which should be carefully considered when relying on local IHC and/or FISH test results.A recent NCCN HER2 testing task force concluded that accurate assessment of HER2 status is essential for decision making in treating invasive breast cancer.Requires that formal validation and concordance testing be performed and reported by testing labsThe task force delineated HER2+, HER2, and borderline status according to specific IHC and FISH test results, and recommended several methods for re-evaluation of borderline cases: additional cell counts, FISH retesting, or retesting by IHC using a FISH-validated method.Another HER2 testing task force, a joint effort by ASCO and CAP, is expected to present its recommendations and guidance in the near future.*There are a number of ways to target EGFR dysregulation.Antibodies against EGFR can act as receptor antagonists and prevent ligand binding, eg, cetuximab.Antibodies may prevent receptor dimerization, eg, trastuzumab (HER2).Antibodies against ligand also block binding, and this approach may be useful when 1 ligand binds to several receptors.Using a small molecule that specifically targets and either reversibly or irreversibly inhibits the tyrosine kinase activity is an approach that may block signaling by all active EGFR forms, including those receptors with mutated or deleted extracellular domains.Erlotinib and gefitinib are 2 ATP-competitive inhibitors of the EGFR tyrosine kinase.Mutations in the tyrosine kinase domain that lead to increased growth factor signaling correlate with increased clinical responsiveness to these TKIs. These mutations demonstrate increased sensitivity to erlotinib and gefitinib. Conjugates of a ligand and a cytotoxic agent (eg, TP-38 and DAB389EGF) or an antibody and a cytotoxic agent (eg, scFv-14e1-ETA fusion toxin) are another approach that may have the advantage of killing the cell after internalization, in addition to inhibiting tyrosine kinase activity.Noonberg SB, Benz CC. Tyrosine kinase inhibitors targeted to the epidermal growth factor receptor subfamily: role as anticancer agents. Drugs. 2000;59:753-767.Erbitux [package insert]. Branchburg, NJ, and Princeton, NJ: ImClone Systems and Bristol-Myers Squibb Company; 2004.Sampson JH, Akabani G, Archer G, et al. Clinical outcome and distribution measure of a recombinant chimeric protein composed of transforming growth factor alpha and a mutated Pseudomonas exotoxin (TP-38) via convection-enhanced microinfusion on a phase I study for malignant brain tumor. Proc Am Soc Clin Oncol. 2003;22:99. Abstract 397.Frankel AE, Liu TF, Thorburn AM, Tatter SB, Willingham MC. Recombinant toxin DAB389EGF produces regressions of human glioma xenografts in nude mice. Proc Am Soc Clin Oncol. 2004;23:220. Abstract 3101.Baselga J. Why the epidermal growth factor receptor? The rationale for cancer therapy. Oncologist. 2002;7(suppl 4):2-8.*Systemic therapy is an essential component of both early stage node-negative breast cancer as well as advanced stage disease. Hormonal therapy, cytotoxic chemotherapy, and the more recently introduced biological therapies are routinely employed in the vast majority of patients with early stage breast cancer. For patients with all stages of breast cancer, systemic therapy has been shown to decrease the relative risk of relapse and mortality. However, there are subsets of patients with a very favorable prognosis and extremely low rate of relapse, in whom the risk reduction results in only a very small absolute benefit. At a recent consensus meeting at St. Galen, Switzerland, an expert panel proposed an algorithm for selection of systemic therapy in early stage breast cancer, based on risk and responsiveness to endocrine therapy *Systemic therapy is an essential component of both early stage node-negative breast cancer as well as advanced stage disease. Hormonal therapy, cytotoxic chemotherapy, and the more recently introduced biological therapies are routinely employed in the vast majority of patients with early stage breast cancer. For patients with all stages of breast cancer, systemic therapy has been shown to decrease the relative risk of relapse and mortality. However, there are subsets of patients with a very favorable prognosis and extremely low rate of relapse, in whom the risk reduction results in only a very small absolute benefit. At a recent consensus meeting at St. Galen, Switzerland, an expert panel proposed an algorithm for selection of systemic therapy in early stage breast cancer, based on risk and responsiveness to endocrine therapy