Adjuvant treatment in early and locally advanced breast cancer By Prof. Dr.Syed Ijaz Hussain Shah (Oncologist)

1. Adjuvant Treatment
in
Early & Locally Advanced Breast Cancer
Prof. (R) Dr. Syed Ijaz Hussain Shah
Sahil Hospital Faisalabad

2. Age-standardised cancer incidence
and mortality
GLOBOCAN 2008
(LARC) (5.10.2012).
International agency for
research on cancer
800000 600000 400000 200000 0 200000 400000 600000 800000
Breast
Lung
Cervix uteri
Colorectal
Stomach
Corpus uteri
Liver
Ovary
Thyroid
Non-Hodgkin lymphoma
Women, all ages (N)
Less developed regionsMore developed regions
Incidence Mortality

3. Over view of Breast cancer
Most common cancer in humanity
Effective Screening available
Early detection-good prognosis
Curable disease
Even in Advanced stages
Good palliation for metastatic pt.

4. Early Breast Cancer
Introduction
Presentation
Diagnosis
Staging
Treatment
EBC-----------T1/2, N0/1, M0
LABC---------T3/4, N2/3, M0/1
MBC----------any TNM distant mets
Indication of adjuvant treatment
Chemotherapy
Radiation therapy
Hormone therapy
Target therapy-Trastuzumab
36% RRR
40% Decrease in death

5.  Surgery ------------ Diagnostic/BCS/MRM
 Chemotherapy for selective patients
 Radiotherapy for selective patients
 Hormone replacement therapy for
HORMONE POSITIVE PATIENTS
 BIOLOGICAL therapy for
HER2/neu over expression patients

6. Early Breast Cancer
EBC-----------T1/2, N0/1, M0

7. SURGERY
 LUMPECTOMY
 WIDE LOCAL EXCISION
 QUARDERANTECTOMY
 SIMPLE MASTECTOMY
 MODIFIED RADICAL MASTECTOMY

8. Adjuvant Treatment for EBC
• Chemotherapy:
• CMF/AC/EC
• Taxanes/Capcitabine/Gemcitabine
• Hormone Therapy for ---------selected patients
• 1--AntiEstrogen
• 2--Aromatase inhibitor for Postmenopausal
patients
• Radiation Therapy for selected patients

11. What is HER Family
Humam Epidermal Growth Factor Receptor
HER1
HER2
HER3
HER4
Only HER2 is significant in Tumor Antigen
Its percentage of positivity in Breast cancer
varies from 14 ----26.
It is associated with poor prognosis and early
recurrence

12. Identifying the right patient: HER2 testing
• High-quality HER2 testing is essential to ensure optimal
identification of patients with HER2-positive tumours eligible
for HER2-targeted therapy
• There are several HER2 testing methods currently used to
detect HER2 protein or gene amplification
– IHC, FISH, CISH, SISH, dual SISH
• With all methodologies, it is essential that all tests are
standardised and validated within each laboratory
Penault-Llorca F, et al. The Breast 2013; 22:200–202;
Wolff AC, et al. J Clin Oncol 2013 (Epub ahead of print).

13. HER2 overexpression / amplification
occurs frequently in breast cancer
Study n Stage HER2 positive, %
Acosta 2001
Ross 2003
Owens 2004a
Press 2005b
Francis 2007
Gown 2008a
Ferno 2007
Penault-Llorca 2008
UK NEQAS 2007
9307
5227
16,092
2502
6512
6604
5043
2079
30,720
I-IV
I-III
I-IV
I-IV
NS
NS
NS
I-III
I-IV
20
24
23
26
17
20
14
16
15
a
Data from high-throughput laboratories; b
BCIRG reference laboratory
EBC, early breast cancer; IHC, immunohistochemistry; FISH, fluorescence in situ hybridisation;
NS, not specified; NEQAS, National External Quality Assessment Scheme;
BCIRG, Breast Cancer International Research Group
Method
IHC / FISH
NS
FISH only
FISH only
IHC
IHC / FISH
IHC / FISH
IHC / FISH
FISH
HER2-positivity rates in Breast Cancer

14. Overexpression of HER2 is
associated with poor prognosis
Pauletti et al 2000
Probability
of survival
(%)
Time (months)
0 12 60 96 120
100
90
80
70
60
50
40
24 36 48 72 84 108
Log-rank p=0.0004
Wilcoxon p=0.0009
EBC patientsa
HER2 negative (n=771)
HER2 positive (n=189)
a
Unselected stage I, II and III breast cancer patients

15. Breast cancer HER2 testing algorithm
If primary ISH testing is used, patients whose tumours overexpress the HER2 protein (i.e. IHC 3+) may not always be identified.
Hanna W & Kwok K. Mod Pathol 2006; 19:481–487.
IHC ISH
(FISH or CISH)
0 3+2+1+
– +
Retest with ISH
(FISH, CISH,
SISH)
– +
Eligible for
HER2-targeted
therapy
Eligible for
HER2-targeted
therapy
Eligible for
HER2-targeted
therapy
Patient tumour sample

16. ASCO/CAP guidelines for HER2 testing*
• An update to the ASCO/CAP guidelines for HER2 testing was
published online on 7 October 2013
• All primary breast cancer specimens and metastases
should have at least one HER2 test performed:
• All newly diagnosed patients with breast cancer must have a
HER2 test performed
• Patients who then develop metastatic disease must have a
HER2 test performed in a metastatic site, if tissue sample is
available
• This should be especially considered for a patient who previously tested
HER2-negative in a primary tumour and presents with disease recurrence
with clinical behaviour suggestive of HER2-positive or triple-negative
disease
* Please note: International guidelines may not be in line with current national guidelines.
ASCO/CAP, American Society of Clinical Oncology/College of American Pathologists.
Wolff AC, et al. J Clin Oncol 2013 (Epub ahead of print).

17. Biology of HER2 and its
importance in breast cancer

18. Trastuzumab: targeting HER2
 Recombinant humanised monoclonal antibody directed against
the extracellular domain of HER2
 Attacks HER2-positive tumours via 4 distinct mechanisms of
action
1. Activation of antibody-dependent cellular
cytotoxicity (ADCC)
2. Prevention of the formation of p95HER2
,
a truncated and very active form of HER2
3. Inhibition of cell proliferation by preventing
HER2-activated intracellular signalling
4. Inhibition of HER2-regulated angiogenesis
3

19. HER2/neu targeted Therapy
(Trastuzumab)
 1=1 year of Herceptin (Trastuzumab) if added to
therapy increased the chance of remaining
cancer free longer1
 2=After completion of chemotherapy
Weekly Trastuzumab with Taxane for 12
weeks followed by Herceptin alone weekly
 3= 52% higher chance of remaining cancer free
longer in the group of women who received
AC→TH
compared with the group that received AC→T

20. continu
surgery and chemotherapy, Herceptin taken every 3
weeks
46% higher chance of remaining cancer free longer
who received Herceptin alone compared with that did
not receive
2% of patients on AC→TH experienced congestive
heart failure (CHF) vs 0.4% without Herceptin

21. contin
36 % Reduction in Risk of
Relapse
40 % decrease in death rate

22. Comparison
Observation for HER2/neu +
Three months /one year
One year/ two years
Trastuzumab/ lapatinib
Trastuzumab plus lapatinib

23. Joint Analysis of
NSABP B-31 and NCCTG N9831
Trastuzumab plus adjuvant chemotherapy for
HER2-positive breast cancer: final planned
joint analysis of overall survival from NSABP
B-31 and NCCTG N9831

24. Joint Analysis of
NSABP B-31 and NCCTG N9831

25. OS with 1 Years of
Herceptin versus observation
Goldhirsch A et al. Proc SABCS 2012;Abstract S5-2.

26. Conclusion
 Results of the HERA study at 8 years of median follow-up
show sustained and statistically significant DFS and OS
benefit for 1 year of trastuzumab versus observation in
analyses despite selective crossover.
 1 year of trastuzumab remains a standard part of adjuvant
therapy for patients with HER2-positive early BC.
 Benefit for 1 year of trastuzumab, compared to observation,
was ---Early recurrence ,more events and less DFS in
observational arm.
Goldhirsch A et al. Proc SABCS 2012;Abstract S5-2.

27. Locally Advanced
Primary Breast Cancer

28. Natural History of Disease
• Most cases of stage III breast cancer
were once stage I breast cancer
 In poor countries, more than half of
patients have locally advanced or
metastatic disease at the time of
diagnosis
 Lack of education
 Lack of screening

29. Clinical Presentation
“Grave clinical signs”
– Skin ulceration
– Skin edema
– Tumor fixation to the chest wall
– Axillary nodes larger than 2.5 cm
– Fixed axillary nodes
•Satellite skin nodules and infraclavicular, internal
mammary, and supraclavicular adenopathy

30. Clinical Presentation
Stage III BreastCancer
Peau d’orange Large mass, edema, and erythema

31. Clinical Presentation of Stage III, Locally
Advanced (Inoperable) Disease
Large primary breast cancer Locally advanced breast cancer

32. Diagnostic Work-Up
•Distinguish benign from malignant disease
•Distinguish noninvasive from invasive disease
• Obtain pathologic diagnosis before treatment:
– Percutaneous image-guided biopsy (preferred)
-Core-needle biopsy
-Fine-needle aspiration
- Excisional biopsy

33. Breast Cancer Up Until Now:
Testing for 1 or 2 Specific Molecules
Estrogen Receptor: 75%Estrogen Receptor: 75%
of breast cancers areof breast cancers are
ER+ER+
HER-2: 20-25% ofHER-2: 20-25% of
breast cancers arebreast cancers are

34. TNM Staging System for
Advanced Breast Cancer
T3 Tumor >5 cm
T4 Invasion of the chest wall or to the skin
(inflammatory breast cancer)
T4a Invasion of the chest wall
T4b Edema, thickening of the skin, or
ulceration of the skin or surrounding skin nodules
T4c Signs of both T4a and T4b
T4d Inflammatory cancer (breast is red,
swollen, and warm)
Greene FL, et al. AJCC Cancer Staging Manual, 6th
ed, 2002.

35. TNM Staging System for
Advanced Breast Cancer (cont.)
N2 Involvement of four to nine axillary lymph
nodes or of internal mammary lymph nodes
without axillary node involvement.
N2a Involvement of four to nine axillary
lymph nodes
N2b Involvement of only internal mammary
lymph nodes

36. TNM Staging System for
Advanced Breast Cancer (cont.)
N3 Involvement of 10 or more
axillary lymph nodes or of the infraclavicular
lymph nodes or of the internal mammary
nodes with axillary node involvement
N3a Involvement of 10 or more axillary
lymph nodes or of the infraclavicular lymph
nodes
N3b Involvement of the internal mammary
nodes and axillary nodes
N3c Involvement of the supraclavicular
nodes

37. Stage Classifications for Locally
Advanced Breast Cancer
Stage IIB T2 N1 M0
T3 N0 M0
Stage IIIA T0 N2 M0
T1 N2 M0
T2 N2 M0
T3 N1 M0
T3 N2 M0

38. Stage Classifications for Locally
Advanced Breast Cancer (cont.)
Stage IIIB T4 N0 M0
T4 N1 M0
T4 N2 M0
Stage IIIC Any T N3 M0
Stage IV Any T Any N M1

39. Multidisciplinary Cancer Breast Management
Survival According to Treatment
Treatment
No. of
Patients
5-Yr. Survival
(%)
Surgery only 2,453 36
Radiation only 2,386 29
Surgery plus radiation 4,249 33
Chemotherapy, surgery, and
radiation
1,923 63
Giordiano SH. Oncologist. 2003;8:521-530.

40. Personalizing Treatment toPersonalizing Treatment to
the Specific Tumorthe Specific Tumor
Multidisciplinary Cancer Breast Management
Multidisciplinary Cancer Breast Management

41. Multidisciplinary Cancer Breast Management
Systemic Therapy for Breast Cancer
Goals:
Attain cure, prevent recurrence, eradicate micrometastases
Appropriate treatments:
Tamoxifen or aromatase inhibitors for postmenopausal women
Ovarian ablation
Chemotherapy
Monoclonal antibody therapy
Supportive care

42. Multidisciplinary Cancer Breast Management
Chemotherapy for Breast Cancer
•Improves disease-free and overall survival
•Anthracycline-based combinations are better than
combination of cyclophosphamide, methotrexate, and
fluorauracil (CMF)
•Taxane-based combinations are more effective in the
adjuvant setting
•Trastuzumab in the adjuvant setting improves disease-
free and overall survival

43. Multidisciplinary Cancer Breast Management
Neoadjuvant Chemotherapy (cont.)
•Goals:
– Decrease tumor size
– Minimize surgery
– Establish tumor sensitivity
•Appropriate treatments:
– Chemotherapy
– Tamoxifen or aromatase inhibitors
– Radiation therapy

44. Multidisciplinary Cancer Breast Management
Clinical Rationale for Preoperative
Chemotherapy
•Excellent response rates for locally advanced
breast cancer
• Efficacy of adjuvant chemotherapy for node-
negative breast cancer
• Equivalent survival for breast-conserving
surgery and mastectomy

45. Multidisciplinary Cancer Breast Management
Advantages of
Neoadjuvant Chemotherapy
•Increased rate of breast-conserving surgery
•Earlier treatment of micrometastases
•Treatment serves as in vivo chemosensitivity
assay
•Improved rates of local control and disease-free
survival

46. Multidisciplinary Cancer Breast Management
Factors Influencing Decision to Use
Neoadjuvant Chemotherapy in Operable
Breast Cancer
•Does the patient need adjuvant
chemotherapy based on information known
prior to surgery?
•Would neoadjuvant chemotherapy
potentially alter the extent of resection?
•Does the patient desire breast
preservation?
•Would treatment benefit from knowledge of
in vivo chemosensitivity?

47. NSABP B-18 Trial: Schema
OperableOperable BreastBreast CancerCancer
•Stratification
•• Age
•• Clinical tumor size
•• Clinical node
status
OperationOperation AC x 4AC x 4
++ TAMTAM ifif >50>50 yrs.yrs.
AC x 4AC x 4
++ TAMTAM ifif >50>50 yrs.yrs. OperationOperation

48. Multidisciplinary Cancer Breast Management

49. NSABP B-27 Trial
Eligibility: Operable Breast Cancer
• Diagnosis by fine-needle aspiration or core biopsy
• Palpable on physical examination
(T1c-3 N 0, M 0 / T 1-3, N 1, M 0)
• Movable in relation to chest wall and skin
• Nodes of any size but not fixed to each other or to
adjacent structures
• No arm edema

50. Multidisciplinary Cancer Breast Management

51. Multidisciplinary Cancer Breast Management
NSABP B-27 Trial (cont.) Treatment Regimen
Chemotherapy: doxorubicin, 60 mg/m2
cyclophosphamide, 600 mg/m2
Docetaxel: 100 mg/m2
Tamoxifen: 20 mg, orally, daily for five years
(beginning on day 1 of chemotherapy)
Radiation: Only for patients who had
lumpectomy; done after surgery (arms I and II) and after
treatment with docetaxel) (arm III)

52. Weekly (wkly) paclitaxel (P) followed by FAC as primary systemic chemotherapy (PSC) of operable breast cancer
improves pathologic complete remission (pCR) rates when compared to every 3-week (Q 3 wk) P therapy (tx)
followed by FAC- final results of a prospective phase III randomized trial.
Marjorie C Green, Aman U Buzdar, Terry Smith, Nuhad K Ibrahim, Vicente Valero, Marguerite Rosales, Massimo
Cristofanilli, Daniel J Booser, Lajos Pusztai, Edgardo Rivera, Richard Theriault, Cynthia Carter, Sonja E Singletary,
Henry M Kuerer, Kelly Hunt, Eric Strom, Gabriel N Hortobagyi
Proc Am Soc Clin Oncol 21: 2002 (abstr 135)
Pathologic Complete Remission
Rates (Breast and Lymph Nodes) :
Weekly vs. Q 3 Week Paclitaxel
Node Positive Node Negative
Weekly (n = 50) Q 3 Week (n= 51) Weekly (n = 68) Q 3 Week (n = 67)
pCR 14 (28%) 7 (13.7%) 20 (29.4%) 9 (13.4%)
Weekly Paclitaxel is superior to q 3 weeks.

53. Multidisciplinary Cancer Breast Management

54. Multidisciplinary Cancer Breast Management

55. Multidisciplinary Cancer Breast Management

56. Endocrine
Therapy

57. Drugs Targeting Estrogen and It’sDrugs Targeting Estrogen and It’s
Receptor in Breast CancerReceptor in Breast Cancer
EstrogeEstroge
nn
CellCell
GrowthGrowth
andand
DivisioDivisio
nn
Estrogen
Receptor
SERMS (tamoxifen,SERMS (tamoxifen,
raloxifene), SERDSraloxifene), SERDS
(fulvstrant)(fulvstrant)
AromataseAromatase
inhibitors,inhibitors,
ovarianovarian
suppressionsuppression

58. Aromatase Inhibitors
Adrenal HormonesAdrenal Hormones
CortisolCortisol AndrostenedioneAndrostenedione AldosteroneAldosterone
EstradiolEstradiol
TestosteroneTestosteroneEstroneEstrone
Aromatase inhibitorsAromatase inhibitors
block post-menopausalblock post-menopausal
estrogen productionestrogen production
Anastrozole (Arimidex)Anastrozole (Arimidex)
Letrozole (Femara)Letrozole (Femara)
ExemestaneExemestane
(Aromasin)(Aromasin)

59. Multidisciplinary Cancer Breast Management

60. Multidisciplinary Cancer Breast Management

61. Multidisciplinary Cancer Breast Management

62. Letrozole Is More Effective Neoadjuvant Endocrine Therapy
Than Tamoxifen for ErbB-1– and/or
ErbB-2–Positive, Estrogen Receptor–Positive Primary Breast
Cancer: Evidence From a Phase III
Randomized Trial
By Matthew J. Ellis, Andrew Coop, Baljit Singh, Louis Mauriac, Antonio Llombert-Cussac, Fritz Ja¨nicke, William
R. Miller, Dean B. Evans, Margaret Dugan, Carolyn Brady, Erhard Quebe-Fehling, and Mieke Borgs
J Clin Oncol 19:3808-3816.

63. Conclusions
 Neoadjuvant therapy:
 Increases the likelihood of breast conservation
somewhat.
 Does not adversely affect survival excepting a
small risk of locoregional failure.
 More is likely better – i.e. add the taxane
 Endocrine receptor status will affect the outcome
and may need to be treated upfront, but chemo
has more robust data.
 Randomized comparison of endocrine vs chemo
vs both is currently lacking for the ER/PR + pt.

64. Does a cCR need surgery?
 Is Surgery Necessary After Complete Clinical
Remission Following Neoadjuvant Chemotherapy for
Early Breast Cancer?
 By A. Ring, A. Webb, S. Ashley, W.H. Allum, S. Ebbs, G. Gui, N.P. Sacks, G. Walsh, and I.E.
Smith
 J Clin Oncol 21:4540-4545

66. MBC

67. Surgery
no role in cure
Only palliative

68. Chemotherapy
Hormone Therapy
Biological Therapy
EFS 20-30%
CR less than 5%

69. Radiation Therapy
Palliation Only

70. THANKS