Dr.Sandip Kumar Barik

GONADAL EXTRAGONADAL Adipose tissue brain, skin, bone Blood vessels, placenta Endometrium

It is intra-nuclear type of receptor2 forms - ER-alpha ER-betaER-alpha – Gene found on chromosome 6 endometrium, breast cell, ovarian stromal cell,

hypothalamus.ER-beta – gene found on chromosome 14 kidney, bone, brain, heart, lungs, intestinal cells, prostate, endothelial cells.

Intranuclear steroid receptor. Encoded by single gene PGR on ch.11q22. Exits in 2 forms 1.PR-A – It oppose estrogen induced proliferation 2.PR-B – It cause epithelial cell proliferation in synchronous with estrogen or estrogen alone can stimulate it

LIGAND BINDING ASSAY Estrogen – I-125 estradiol

Progesteron – H3-R5020 considered to be positive if ER>3fmol/mg of

protein

IHC – Antibodies against receptor are used

Receptor +ve if score >2

NO OF +VE CELLS INTENSITY OF STAINING

None o O no staining

< 1/100 1 1 weak

1/100 – 1/10 2 2 Intermediate

1/10 - 1/3 3 3 strong

1/3 - 2/3 4

> 2/3 5

Receptor status Pre menopausal Post menopausal

ER/PR + 45% 63%

ER/PR - 28% 17%

ER+ only 12% 15%witteff jl.steroid harmone receptors in breast cancer. cancer 53:630,1984

ER+PR+ (25%) ER+PR- (7.4%)

ER-PR+ (21.1%) ER-PR- (46.5%)

Receptor status in Indian population

Tata Memorial Hospital Breast. 2000 Oct;9(5):267-70

Gene located on chromosome 15 Member of cytP450 enzyme Present in ER It has two transcript variant

Selective Estrogen Receptor Modulator(SERM)

1. Tamoxifen

2. Tormemifene

3. Raloxifen Non Steroidal Inhibitors of Aromatase1. Anastrazole

2. Letrozole

3. Fadrazole Steroidal Irreversible Inhibitors of Aromatase1. Exemestane Pure Estrogen Receptor Antagonists1. Fulvestrant

Estrogen

Ovaries Peripheral Sites: adrenal gland, liver, muscle, fat

Aromatase Inhibitors

Tamoxifen

X

Postmenopausal

Ovarian Suppression

GnRH inhibitors or Ovarian removal

Premenopausal

Cancer Cell

ER

ER

Fulvestrant

Tamoxifen

Tamoxifen (10 – 20 mg BD) Raloxifene ( 60 mg OD)

S/E :-- hot flushes,- fluid retention - vaginal discharge- Irregular menses- Skin rashes- DiarrhoeaPotential risk of developing-- thrombosis- ocular toxicities- endometrial cancer,endometrial

hyperplasia,endometrial polyp

Nonsteroidal Anastrazole (1 mg OD) Letrazole (2.5 mg OD) Steroidal Exemestane (25 mg OD)

S/E- skin reactions, jaundice hot flashes, back pain insomnia.

Fulvestrant (250 mg IM monthly )

Side/effects gastrointestinal symptoms headache, back pain, vasodilatation (hot flushes), pharyngitis.

1 Surgical

2 Radiation

3 Hormonal

LHRH agonists Leuprolide Goserlin

The upper border - inferior sacroiliac joint.

The lower border – mid-obturator foramen.

Lateral borders - 1 cm laterally to the pelvic sidewall

Dose – 14 - 20 Gy /7 -10 #

• Leuprolide (11.25 mg I.M every 3 month)

• Goserlin (6.6 mg s/c every 2 month)

S/E:- Nausea vomiting Sweating , Breast atropphy, Severe polydipsia Polyurea, Ammenorhea.

Cells in LCIS are usually Estrogen receptor positive

Hence Tamoxifen is indicated in high risk patients

DCIS – estrogen receptor +ve in 70% of DCISTrial

groupNo of pt Follow

upNo tam With tam LOCAL RECURRENCE (%)

P value

NSABP B - 24

1798 7 YR 11.1 7.7 .02

UKCCCR 1576 4.38 YR 15 13 .42

In this trial, ovarian ablation or suppression did not add to the benefits of 5 years of tamoxifen treatment or to those of

tamoxifen plus chemotherapy in terms of relapse-free survival

or overall survival rates

Even in the subgroup of women younger than 40 years who

received chemotherapy, the majority of whom would have retained ovarian function, there appears to be no gain from ovarian ablation or suppression in combination with 5 years of tamoxifen treatment.

What to do ???????

Three scenarios are currently considered:1. Monotherapy with AI for 5yrs vs Tamoxifen.

2. Switching or sequencing from tamoxifen to AI or reverse halfway through 5 yrs of treatment.

3. Extended adjuvant therapy randomising to AI or placebo/no furthur therapy after completion of about 5 yrs of Tamoxifen.

PRIMARY ADJUVANT TRIAL

EXTENDED ADJUVANT TRIAL

Anastrozole is a reasonable choice as initial therapy because of

Improved DFS Decreased incidence of

Thromboembolic events Decreased Ca Endometrium

Letrozole therapy after 5 years of adjuvant tamoxifen is tolerable and effective

Letrozole improved DFS and distant DFS across all age groups Significant improvements vs

placebo among patients ≤ 60 yrs of age

OS improved in those with node positive disease(MA17 trial)

The superiority of AI in reducing recurrence is manifested early in the treatment and a strategy of randomization after 2-3 yrs of tamoxifen will exclude women with the most endocrine resistant tumors.

Compared with 5 yrs of tamoxifen a switch from tamoxifen to AI after 2-3 yrs improved DFS in all studies.

Thus the data so far suggests that initiation of adjuvant endocrine therapy in post menopausal women should be with an AI and that continuing to 5 years with same therapy or switching to tamoxifen after 2-3 yrs appear equally efficacious.

Member of EGFR family Also k/a CD340 & p185 Her2 is a cell membrane surface bound receptor

tyrosine kinase Her2 gene is a proto-oncogene located at long

arm of ch.17. Neu terminology is used, as it was derived

from a rodent glioblastoma cell line, a type of neural tumor .

15-20% of breast cancers have an amplification of Her2neu gene.

Over-expression of this receptor in breast cancer is associated with increased disease recurrence and worse prognosis.

IHC

FISH – Probe tagged with fluorescent label if >2 fluorescent light come out cell considered to be overexpressing

HER - 2

SCORING GRADING

0 Absence of staining or < 10% cells are +ve

1 Weak & incomplete staining in > 10% cells

2 Weak & moderate staining in > 10 % cells

3 Strong & complete staining in >10 % cells

Bilous M, et al. Mod Pathol 2003;16:173–82

FISH

Patient Tumour Sample

Transtuzumab

therapy

+–2+

3+

1+0

+–

FISH

IHC

Transtuzumab therapy

Transtuzumab

therapy

TRANSTUZUMAB(herceptin)-- Monoclonal antibody.

- Acts on cell membrane bound her 2 receptor.

- Duration- 1 yr.

- Initial trastuzumab dose of 4 mg/kg i.v. over 90 minutes, followed by a weekly maintenance dose of 2 mg/kg i.v. administered over 30 minutes if the initial dose is well tolerated

- Toxicity- cardiac dysfunctioning.

chest pain or heavy feeling, pain spreading to the arm or shoulder, nausea, sweating, general ill feeling;

fast or pounding heartbeats; feeling short of breath, even with mild exertion; swelling, rapid weight gain; cough or wheezing; white patches or sores inside your mouth or on your lips;

or fever, chills, body aches, flu symptoms. Less serious side effects are more likely to occur, such as: nausea, vomiting, diarrhea; sore throat, sinus pain; joint or muscle pain, back pain; headache; tired feeling.

No prior anthracyclines Prior anthracyclines

Paclitaxel(n=96)

Herceptin® + paclitaxel(n=92)

AC(n=138)

Herceptin® + AC(n=143)

MBC HER2 IHC 2+/3+ (CTA) No prior CT for MBC Measurable disease KPS 60%

Patients (n=469)

Slamon DJ, et al. N Engl J Med 2001;334:783–92

Adding Transtuzumab to paclitaxel improves all clinical outcome parameters ORR (from 17 to 49%*) TTP (from 3 to 7 months*) OS (from 18 to 25 months*)

Transtuzumab adds little to the toxicity profile of paclitaxel

Transtuzumab plus paclitaxel should be considered as first-line therapy in HER2-positive MBC

*IHC 3+ patients

Large adjuvant trials have recently

established its role in the adjuvant setting

in 5 RCTs:

- HERA

- NSABP B31

- NCCTG N9831

- BCIRG 006

- FinHer

Adjuvant Transtuzumab Therapy

Women with HER-2 POSITIVE invasive Women with HER-2 POSITIVE invasive breast cancer IHC3+ or FISH+ breast cancer IHC3+ or FISH+

centrally confirmedcentrally confirmed

Surgery + (neo)adjuvant chemotherapy (CT) Surgery + (neo)adjuvant chemotherapy (CT) radiotherapy radiotherapy

StratificationStratificationNodal status, adjuvant CT regimen, hormone receptor status and endocrine therapy, age, Nodal status, adjuvant CT regimen, hormone receptor status and endocrine therapy, age,

regionregion

RandomizationRandomization

TrastuzumabTrastuzumab8 mg/kg 8 mg/kg 6 mg/kg 6 mg/kg3 weekly x 2 years3 weekly x 2 years

TrastuzumabTrastuzumab8 mg/kg 8 mg/kg 6 mg/kg 6 mg/kg

3 weekly x 1 year3 weekly x 1 yearObservationObservation

CONCLUSIONSCONCLUSIONS

At one year median follow-up:At one year median follow-up:

• Trastuzumab given every 3 weeks for one year following Trastuzumab given every 3 weeks for one year following adjuvant chemotherapy significantly prolongs DFS and RFS adjuvant chemotherapy significantly prolongs DFS and RFS for women with HER-2 positive early breast cancerfor women with HER-2 positive early breast cancer

• Trastuzumab significantly reduces the risk of distant Trastuzumab significantly reduces the risk of distant metastasesmetastases

• Trastuzumab’s clinical benefits are independent of Trastuzumab’s clinical benefits are independent of patients’ baseline characteristics (nodal status, hormone patients’ baseline characteristics (nodal status, hormone receptor status, ...) and of type of adjuvant chemotherapy receptor status, ...) and of type of adjuvant chemotherapy receivedreceived

Lapatinib(Tykerb):-Dose 1250 mg daily• Inhibits the Tyrosine kinase activity associated with two

oncogenes EGFR1 & EGFR2.

• Approved in combination with capecitabine for treatment of patients with:• Advanced or metastatic breast cancer whose tumor overexpress

HER2 neu.

• Who have received prior therapies with Anthracyclins,Taxanes and Trastuzumab.

Everolimus:(5 mg OD)• Its acts by selectively inhibiting mTOR(mammalian target

of Rapamycin),an intracellular protein kinase .

• Useful for endocrine resistant,hormone receptor positive,Her2 neu negative advanced breast cancer.

• Potentially overcome resistance to endocrine therapy.

• Phase II studies have reported that combination ofmTOR inhibitors with endocrine therapy shows efficacy in pts with advanced disease that progressed after treatment with aromatase inhibitors

The addition of everolimus to exemestane for women with HR positive metastatic Breast cancer is now considered a new therapeutic strategy.

Bevacizumab(binds to VEGF)

Aflibercept(Fusion protein targeting VEGF)

Pertuzumab(blocks HER2 with EGFR,HER3,HER4)

Sorafenib

THANK YOU