This document discusses various treatments for breast carcinoma including chemotherapy, hormonal therapy, and targeted therapy. It provides details on: - The indications for chemotherapy including tumor size, node involvement, and molecular factors. - How prognostic factors like tumor grade and molecular markers help determine treatment. - Studies that helped establish chemotherapy regimens and combinations like adding taxanes or using dose-dense schedules. - The use of neoadjuvant chemotherapy and outcomes seen with complete responses. - Hormonal therapies for hormone receptor positive cancers including tamoxifen, aromatase inhibitors, and ovarian ablation. - Targeted therapies for HER2 positive cancers including trastuzumab and newer agents.

1. Chemotherapy
Hormonal Therapy
Targeted Therapy
- IN BREAST CARCINOMA
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2. Outline
• Chemotherapy
• Evolution
• Adj
• Neo-adj
• Metastatic
• Hormonal therapy
• Targeted therapy
• Treatment guideline - NCCN
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3. Chemotherapy
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4. Indication
• Generally recommended for >1 cm tumors
• Node positive disease.
• Consider for all triple negative tumors,
• Given high rates of recurrence and lack of options
 for targeted or endocrine therapies.
• Risk Stratification for Adjuvant Therapy based on
• Oncotype DX and
• MammaPrint
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5. Various Prognostic Factors
1. Anatomic:
1. Size of tumor
2. Lymph node (LN) involvement
1. The most powerful prognostic factor
2. Histologic:
1. Tumor grade
2. LV Invasion,poorly differentiated
3. Markers of increased proliferation:mitotic index,high
Ki67,elevated S-phase fraction
4.
3. Molecular factors:
1. ER/PR status
2. HER2/neu over expression
3. 21-gene or 70-gene recurrence score
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6. Oncotype Dx: The 21-Gene Assay
• RT-PCR was used to quantify gene expression
• from fixed, parafin-embedded tumor tissue
• Designed to quantify the risk of distant recurrence in patients with
newly diagnosed,eariy stage,LN(-), ER(+) tumors receiving
tamoxifen.
• recurrent score calculated from 0-100
• NSABP trial B-14 ,patients classified according to the recurrent
scores(RS) based on 10 year distant disease free survival into
• high risk(RS 31&above),
• intermediate risk(RS 18 and <31) and
• low risk(RS <18)
• From these studies, 16 genes (+5 reference genes) were selected
that correlated with proliferation and endocrine response
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7. Levels of Gene Expression Determine
Recurrence Score
21-gene assay = 16 outcome-related genes + 5 reference genes
Higher expression levels of
“favorable” genes = ↓ RS
Higher expression levels of
“unfavorable” genes = ↑ RS
A risk score is calculated from 0 -100
Cutoff points chosen based on
Results of NSABP trial B-20
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8. •NCCN guidelines include Oncotype DX® testing in the
treatment-decision pathway for node-negative and
micrometastatic disease
•Adapted from NCCN Practice Guidelines in Oncology – v.1.2010.
1. Tumor 0.6-1.0 cm,
2. Moderately or poorly
differentiated,
3. Intermediate or high
grade, or
4. Vascular invasion
5. Tumor > 1 cm with
favorable or
unfavorable
pathologic features
•Consider
Oncotype
DX
•Hormone receptor-positive, HER2-negative disease
•pT1, pT2, or pT3 and pN1mi
•No test
•RS < 18
•RS 18-30
•RS ≥ 31
•Adjuvant endocrine therapy
•± adjuvant chemotherapy
•Adjuvant endocrine therapy
•endocrine therapy
•± adjuvant chemotherapy
•Adjuvant endocrine
therapy
•+ adjuvant chemotherapy
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9. Mammaprint
• DNA microassay
• consisting of 70 genes regulating
• cell cycle, invasion, metastasis, and angiogenesis.
• Requires fresh tumor tissue
• Gene expression signature that was strongly prognostic for
development of distant metastasis in lymph node negative patients
was identified
• Both ER –negative and ER-positive patients were included
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10. Evolution
• Improvements in disease-free survival (DFS) with
single-agent chemotherapy after radical
mastectomy in the 1970s.
• Polychemotherapy was first evaluated by
Bonadonna
– randomized women with node-positive breast cancer
to 12 monthly cycles of cyclophosphamide,
methotrexate, and 5-fluorouracil (CMF) chemotherapy
– or no further therapy after radical mastectomy
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11. • NSABP B-20 (Fisher et al. 2004):
• 2,306 patients status post sur gery with
pathologically LN−, ER+ breast ca randomized to
• tamoxifen alone vs. tamoxifen + MF chemotherapy
vs. tamoxifen + CMF chemotherapy.
• The addition of chemotherapy to tamoxifen
improved 12-year DFS (HR = 0.52) and OS (HR =
0.78, p = 0.068).
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12. • NSABP-B28 (Mamounas et al. 2005):
• 3,060 LN+ patients randomized to
• AC × 4 ± Paclitaxel.
• Addition of taxane improved 5-year DFS
(72→76%) and LRR, despite delay of RT (9.7 vs.
3.7%).
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13. CALGB 9344 (Sartor et al.2005;Henderson et al. 2003)
• Randomization : Standard dose AC vs. dose escalation
of doxorubicin ± sequential addition of paclitaxel.
• The sequential Continued addition of adjuvant paclitaxel to AC for
LN+ patients
• improves DFS and OS vs. adjuvant AC alone, and further improves
5-year LRC in patients treated with BCS+RT despite delaying RT
delivery.
• No DFS or OS improvement with dose escalation of
doxorubicin.
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14. CALGB 9741 (Citron et al. 2003).
Four arm randomized trial:
• sequential vs. concurrent addition of paclitaxel (T)
to AC chemotherapy, every 3 weeks vs. every 2
week (dose dense) dosing.
• Increased 4-year DFS with dose-dense chemo (82
vs. 75%),
• No difference between sequential or concurrent
delivery.
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15. USOT (Jones et al. 2009):
1,016 Stage I–III patients randomized to AC × 4 vs.
TCx4.
With a median of 7-year follow-up,
TC improved DFS (81 vs. 75%) and OS (87% TC v
82).
TC improved outcomes regardless of age, hormone
receptor, or HER2 expression status.
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17. • Taxane
• CALGB9344: ER-, ER+/Her2+
• NSABP B-28: ER+
• PACS01: ER-/PR+
• BCIRG 001: no difference
• Favored LN 1-3 more than >4
• Anthracycline
• Her2+
• ER- - subset analysis
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18. Principles of Adjuvant Therapy
1. Decrease the risk of recurrence and death from
breast cancer with local therapy alone
2. Endocrine therapy benefits only those with
hormone receptor positive disease
3. Chemotherapy benefits everyone
4. To eradicate “micrometastasis”
5. Combination chemotherapy is more effective than
monotherapy
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19. 6. Adjuvant chemotherapy reduces LR after lumpectomy +
RT
7. Anthracycline (doxorubicin)-based regiments (± taxanes
for high-risk disease) have been associated with superior
outcomes(USOT 9735, Jones et al. 2009).
8. Dose-dense regimens may have increased efficacy in
highrisk patients.
Principles of Adjuvant Therapy
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27. Her 2 +
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33. Principles of Neoadjuvant
chemotherapy
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36. Neoadjuvant chemotherapy is considered standard of
care in high-risk populations such as
• young patients and/or
• advanced-stage disease,
• Stage IIb–III breast
• Inflammatory ca
• T4, N3, bulky or matted N2
Principles of Neoadjuvant
chemotherapy
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37. Principles of Neoadjuvant
chemotherapy
Typically, similar indications as adjuvant chemotherapy
Advantages of neoadjuvant chemotherapy:
• assessment ofdisease response,
• increased rate of BCT
• Neoadjuvant chemotherapy converts 20–30% of patients
initially ineligible for BCT to eligible
• Complete clinical (cCR) and pathological response rates
• 20–40% achieve cCR , 10–20% achieve pCR
• Alow time for genetic testing
– Diminished response noted in ER+, low grade, or invasivelobular cancers
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38. In HER2 positive
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39. In HER2 positive
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40. Metastatic breast cancer
• Except in rare cases stage IV cancer is
considered incurable
• Focus of treatment should be on palliation of
disease related symptoms
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46. Pregnant and Recently Postpartum
• 1/3000 pregancies or 1-4% of BrCa in women under 50
• Greatest risk from chemo in 1st trimester
• In 2nd/3rd trimester still carries risk of IUGR, etc
 Mostly AC or FAC, little data for taxanes
 Don’t use Mtx
 Generally, don’t recommend delaying chemo
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48. Hormonal Therapy
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49. Rationale for endocrine therapy of breast
cancer
Risk factors for Br Ca include prolonged estrogen
exposure states such as
early menarche,
late menopause,
nulliparity and
estrogen replacement therapy.
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50. ESTROGEN RECEPTOR
Protein molecule- mainly in nucleus
small amount in cytoplasm and plasma memb
2 isoforms – ERά and ER β
ER ά - predominates in uterus, breast, pituitary, bone,
CNS,CVS
ER β - predominates in prostate, ovary,
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51. Mech. of carcinogenesis
• ER is overexpressed in as many as 70% of breast
cancers .
• Estrogen exerts its actions by both
• Genomic - through nuclear receptors
• Nongenomic - cytoplsmic receptors.
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52. NSABP B-14 (Fisher et al. 2004):
• 2,644 patients status-post surgery for breast ca
(pathologically LN−, ER+) randomized to
• tamoxifen × 5 years vs. placebo.
• Adjuvant tamoxifen improved 15-year DFS (HR
= 0.58) and OS (HR = 0.80).
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53. ATAC Trial (2002; Lancet 2005): Arimidex, Tamoxifen, Alone or in Combination
• 9,366 postmenopausal patients (both ER +/-)
status-post definitive therapy for earlystage breast
ca randomized to anastrozole, tamoxifen, or both
given concurrently.
• Anastrozole alone improved 3-year DFS compared
with tamoxifen (89 vs. 87%) or both (87%).
• Benefit observed only in ER+ patients.
• Anastrozole better tolerated with respect to side-
effects.
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54. Goss (Goss et al. 2003):
• 5,187 postmenopausal patients (98% ER+)
status-post definitive therapy and adjuvant
tamoxifen × 5 years for early-stage breast ca
randomized to letrozole (2.5 mg) or placebo
daily × 5 years.
• Addition of letrozole improved 4-year DFS
(87→93%).
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55. BIG 1-98249
• 8028 patients on RCT with 4 groups
– Tamoxifen (Tam) x 5 yr;
– Letrozole (Let) x 5 yr;
– Tam x 2 yr → Let x 3 yr
– Let x 2yr → Tam x 3 yr
• 51 months follow up the use of upfront letrozole for
5 years resulted in a significant reduction in the risk
of an event (HR.82; P = .007) compared with
upfront tamoxifen for 5 years
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56. Types of endocrine therapy
ovarian suppression /ablation
surgical oopherectomy
radiation ,,
medical ,, ,,
 anti estrogen drugs.
SERM, SERD, AI
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57. Drugs used in Hormone Rx
• SERD –
• Fulvestrant.
• SERM –
• Tamoxifen
• Droloxifene
• Toremifene
• Raloxifene
• AI -
• EXEMESTANE
• LETROZOLE
• ANASTROZOLE
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59. Mechanism of Action
ANDROSTENEDIONE ESTRONE
AROMATIZATION ESTRIOL
TESTOSTERONE ESTRADIOL
Aromaters inhibitors
Type 1 - steroidal and irreversible
e.g.. EXEMESTANE
Type 2 - nonsteroidal and reversible
e.g.. LETROZOLE ANASTROZOLE
In peripheral tissues
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60. NCCN guidelines.
All pts. c. invasive Br. Cancer, who are ER or PR +ve
should be considered for adj. hormonal therapy,
regardless of
Age
LN status
Her 2 status
Adj.chemo given or not
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61. Radiation oopherectomy
• Radiation used for ablation of ovarian function.
• Given in pts. c. medical c/i for tamoxifen,
• Can be considered in young highrisk pt. completd
5 yrs of tamo. or who progressed while on
tamoxifen.
• Now, medical oopherectomy is preferred.
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62. Radiation oopherectomy
Target vol. is true pelvis.
Sup.brdr. ----- inferior brdr. of S1 jt.L5/S1
Infr. brdr ----- lower brdr. of obturator fora.
Lateral .. ---- bony pelvic sidewall
 AP – PA portals.
 usually 12 x 12 cm field
 Dose. 15 Gy in 5 # given
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63. Duration ?
Scottish Adjuvant Tamoxifen Trial
• patients who were disease free at 5 years were
randomly assigned either to stop taking tamoxifen
or to continue taking it indefinitely until relapse or
death.
• With a median follow-up of 15 years,
• No additional benefit was observed in taking
tamoxifen beyond 5 years.
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64. • Despite the preponderance of evidence suggesting
that extension of tamoxifen therapy beyond 5 years
is not beneficial, two large ongoing trials,
• ATLAS (Adjuvant Tamoxifen-Longer Against
Shorter) and
• aTTom (Adjuvant Tamoxifen Treatment-Offer
More) may offer new insight into the optimal
duration of tamoxifen therapy.
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65. Cdk @
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66. Targeted Therapy
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67. • HER-2 is overexpressed or gene amplified in
20% to 25% of breast cancers.
• The anti-HER-2 monoclonal antibody
trastuzumab targets HER-2-positive tumors,
– inhibits proliferation, and
– induces cell death
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69. NSABP B-31 & NCCTG N9831 (Romond et al. 2005):
• 3,351 patients with resected LN+ or high-risk LN−,
HER2+ breast cancer randomized to
• ACT chemo (doxorubicin, cyclophosphamide, and
paclitaxel) vs. chemo + trastuzumab (ACT-H).
• Trastuzumab increased 3-year DFS (75→87%) and
OS (92→94%), but was associated with increased
risk of heart failure or cardiac death (3–4%).
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70. HERA BIG 01-01 (Piccart-Gebhart et al. 2005):
• 5,090 patients status postsurgery ± RT and
neoadjuvant or adjuvant chemo ± HT (if ER/PR+)
with HER2 overexpression randomized to
• Observation , 1-year trastuzumab (q3 week), or 2-
year trastuzumab.
• On interim analysis, trastuzumab × 1 year
improved 2-year DFS (77→86%), but no difference
in OS (95–96%).
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71. Pertuzumab - perjeta
• inhibition of heterodimerization of HER2
with other HER family members, including
EGFR, HER3, and HER4
• Pertuzumab binds to a different HER2 epitope
than trastuzumab
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72. • The dosage of pertuzumab used in the pivotal phase III
CLEOPATRA (Clinical Evaluation of Pertuzumab and
Trastuzumab) trial was as follows: IV 840 mg loading
dose followed by IV 420 mg every three weeks
• MARIANNE (advanced breast cancer),
• NEOSPHERE (early breast cancer),
• TRYPHAENA (HER2-positive stage II/III breast cancer) and
• APHINITY (HER2-positive nonmetastatic breast cancer)
– On going trials
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73. • Ado-trastuzumab emtansine
– an antibody-drug conjugate consisting of
the monoclonal antibody trastuzumab (Herceptin)
linked to the cytotoxic agent emtansine (DM1)
– EMILIA clinical trial
» for treatment of HER2-positive mBC , treated previously
with trastuzumab and a taxane (paclitaxel or docetaxel),
and who have already been treated for mBC or developed
tumor recurrence within six months of adjuvant therapy
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74. EMILIA study,
• 991 people with unresectable, locally advanced or
metastatic HER2-positive breast cancer who had
previously been treated with trastuzumab and taxane
chemotherapy
• a phase III clinical trial that compared
• trastuzumab emtansine Vs capecitabine (Xeloda)
plus lapatinib (Tykerb).
• This trial showed improved progression-free survival in
patients treated with trastuzumab emtansine (median
9.6 vs. 6.4 months), along with improved overall
survival (median 30.9 vs. 25.1 months)
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75. Lapatinib
• Inhibits the tyrosine kinase activity associated with
two oncogenes,
– EGFR (epidermal growth factor receptor) and
– HER2/neu (Human EGFR type 2)
• ER+/EGFR+/HER2+ breast cancer patients and in
patients who have HER2-positive advanced breast
cancer that has progressed after previous treatment
with other chemotherapeutic agents, such
as anthracycline, taxane-derived drugs, or trastuzumab
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76. Adjuvant Lapatinib and/or Trastuzumab Treatment
Optimisation (ALTTO) trial
• an international research study that will randomize
more than 8000 patients
– to receive trastuzumab alone for 52 weeks,
– lapatinib alone for 52 weeks,
– trastuzumab for 12 weeks, followed by a 6-week
break, followed by lapatinib for 34 weeks, or
– lapatinib in combination with trastuzumab for 52
weeks
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77. Olaparib (AZD2281)
• an oral PARP inhibitor 600mg o.d
• in the treatment of patients with metastatic
previously treated breast
• The use of inhibitors of poly (ADP-ribose)
polymerase in triple negative metastatic breast
cancer has been reported in a randomized phase II
trial of gemcitabine/carboplatin with or without
PARP inhibition
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78. Treatment guideline
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79. • Adj
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85. • Neo-adj
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89. • Metastatic
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95. • Thnak yuo
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