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gives in a nut shell about the hormonal therapies in breast carcinoma and current practice in oncology
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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
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