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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 receptor
2 forms - ER-alpha
ER-beta
ER-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 Aromatase
1. Anastrazole
2. Letrozole
3. Fadrazole
 Steroidal Irreversible Inhibitors of Aromatase
1. Exemestane
 Pure Estrogen Receptor Antagonists
1. 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
- Diarrhoea
Potential 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 DCIS
Trial group No of pt Follow up No 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 invasiveWomen 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) ±± radiotherapyradiotherapy
StratificationStratification
Nodal 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
TrastuzumabTrastuzumab
8 mg/kg8 mg/kg  6 mg/kg6 mg/kg
3 weekly x 2 years3 weekly x 2 years
TrastuzumabTrastuzumab
8 mg/kg8 mg/kg  6 mg/kg6 mg/kg
3 weekly x 1 year3 weekly x 1 year
ObservationObservation
CONCLUSIONSCONCLUSIONS
At one year median follow-up:At one year median follow-up:
• Trastuzumab given every 3 weeks for one year followingTrastuzumab given every 3 weeks for one year following
adjuvant chemotherapy significantly prolongs DFS and RFSadjuvant 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 distantTrastuzumab significantly reduces the risk of distant
metastasesmetastases
• Trastuzumab’s clinical benefits are independent ofTrastuzumab’s clinical benefits are independent of
patients’ baseline characteristics (nodal status, hormonepatients’ baseline characteristics (nodal status, hormone
receptor status, ...) and of type of adjuvant chemotherapyreceptor 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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Hormonal and targeted therapy dr sandip

  • 2.  GONADAL  EXTRAGONADAL Adipose tissue brain, skin, bone Blood vessels, placenta Endometrium
  • 3.
  • 4. It is intra-nuclear type of receptor 2 forms - ER-alpha ER-beta ER-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.
  • 5.
  • 6.  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
  • 7.  LIGAND BINDING ASSAY Estrogen – I-125 estradiol Progesteron – H3-R5020 considered to be positive if ER>3fmol/mg of protein
  • 8.  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
  • 9. 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
  • 10.
  • 11.  Gene located on chromosome 15  Member of cytP450 enzyme  Present in ER  It has two transcript variant
  • 12.  Selective Estrogen Receptor Modulator(SERM) 1. Tamoxifen 2. Tormemifene 3. Raloxifen  Non Steroidal Inhibitors of Aromatase 1. Anastrazole 2. Letrozole 3. Fadrazole  Steroidal Irreversible Inhibitors of Aromatase 1. Exemestane  Pure Estrogen Receptor Antagonists 1. Fulvestrant
  • 13. 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
  • 14. Tamoxifen (10 – 20 mg BD) Raloxifene ( 60 mg OD)  S/E :- - hot flushes, - fluid retention - vaginal discharge - Irregular menses - Skin rashes - Diarrhoea Potential risk of developing- - thrombosis - ocular toxicities - endometrial cancer,endometrial hyperplasia,endometrial polyp
  • 15. 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.
  • 16. Fulvestrant (250 mg IM monthly )  Side/effects  gastrointestinal symptoms  headache,  back pain,  vasodilatation (hot flushes),  pharyngitis.
  • 17. 1 Surgical 2 Radiation 3 Hormonal LHRH agonists Leuprolide Goserlin
  • 18.  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 #
  • 19. • 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.
  • 20.
  • 21.
  • 22.  Cells in LCIS are usually Estrogen receptor positive  Hence Tamoxifen is indicated in high risk patients  DCIS – estrogen receptor +ve in 70% of DCIS Trial group No of pt Follow up No 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
  • 23.
  • 24. 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.
  • 25. What to do ???????
  • 26.  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.
  • 27.
  • 28. 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)
  • 29.
  • 30.  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.
  • 31.
  • 32.
  • 33.
  • 34.
  • 35.  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.
  • 36.
  • 37.
  • 38.  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
  • 39. 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
  • 40.  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.
  • 41.  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.
  • 42. 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
  • 43.  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
  • 44.  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
  • 45. Women with HER-2 POSITIVE invasiveWomen 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) ±± radiotherapyradiotherapy StratificationStratification Nodal 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 TrastuzumabTrastuzumab 8 mg/kg8 mg/kg  6 mg/kg6 mg/kg 3 weekly x 2 years3 weekly x 2 years TrastuzumabTrastuzumab 8 mg/kg8 mg/kg  6 mg/kg6 mg/kg 3 weekly x 1 year3 weekly x 1 year ObservationObservation
  • 46. CONCLUSIONSCONCLUSIONS At one year median follow-up:At one year median follow-up: • Trastuzumab given every 3 weeks for one year followingTrastuzumab given every 3 weeks for one year following adjuvant chemotherapy significantly prolongs DFS and RFSadjuvant 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 distantTrastuzumab significantly reduces the risk of distant metastasesmetastases • Trastuzumab’s clinical benefits are independent ofTrastuzumab’s clinical benefits are independent of patients’ baseline characteristics (nodal status, hormonepatients’ baseline characteristics (nodal status, hormone receptor status, ...) and of type of adjuvant chemotherapyreceptor status, ...) and of type of adjuvant chemotherapy receivedreceived
  • 47.  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.
  • 48.  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
  • 49. The addition of everolimus to exemestane for women with HR positive metastatic Breast cancer is now considered a new therapeutic strategy.
  • 50.  Bevacizumab(binds to VEGF)  Aflibercept(Fusion protein targeting VEGF)  Pertuzumab(blocks HER2 with EGFR,HER3,HER4)  Sorafenib

Editor's Notes

  1. Limitations of the data: Timing of randomization, longest median follow up data is 8 years, different definitions of study end points.
  2. Core slide kit: pivotal trial, combination therapy Pivotal trial Phase III Breast cancer, metastatic, first line Breast cancer, metastatic Herceptin combination Trial design Anthracyclines Paclitaxel
  3. Core slide kit: pivotal trial, combination therapy Pivotal trial Phase III Herceptin combination Efficacy Survival TTP Conclusions Breast cancer, metastatic, first line