Overview of the advances in systemic management of locally advanced breast cancer.

1. Advances in The Management of
Breast Cancer
what we have new in 2012?
Mohamed Abdulla M.D.
Prof. of Clinical Oncology
Cairo University
Khartoum 05/07/2012

2. Disease Epidemiology
• Breast cancer is the most frequently diagnosed cancer and a leading
cause of cancer death among females in the world1
– Accounts for 23% (1.38 million) of the total cancer cases1
– Accounts for 14% (458,400) of cancer deaths1
• 1 in 8 women in Western developed countries will be afflicted with
breast cancer in her life time2
• Approximately 5% of all breast cancer is classified as metastatic at time
of diagnosis2
– 5-year survival rate of 23.3% – significantly lower than localized and regional breast
cancer (98.3% and 83.5%, respectively)2
• Most important risk factors – female gender and increasing age3
• Prognostic factors for newly diagnosed advance breast cancer (BC)
– Grade 3 disease, increasing age, hormone receptor-negative disease, and no breast
conserving surgery or mastectomy4
1Jemal A, et al. CA Cancer J Clin. 2011;61:69-90; 2American Cancer Society. Breast Cancer Facts & Figures 2009-2010. www.cancer.org; 3National Comprehensive Cancer Network. NCCN
Clinical Practice Guidelines in Oncology. V2.2011. http://www.nccn.org/professionals/physician_gls/f_guidelines.asp. Assessed September 4, 2011; 4Dawood S, et al. J Clin Oncol.
2008;26(30):4891-4898.

3. Stages of Breast Cancer
Stage Primary Tumor Nodes Metastases
Stage 1A ≤ 20 mm None None
Stage 1B ≤ 20 mm Nodal Micrometastases
(>0.2 mm <2.0 mm)
None
Stage IIA ≤ 20 mm
> 20 mm ≤ 50 mm
N1
None
None
None
Stage IIB > 20 mm ≤ 50 mm
> 50 mm
N1
None
None
Stage IIIA ≤ 50 mm
> 50 mm
N2
N1 or N2
None
Stage IIIB Extension to chest
wall and/or skin
N0 - N2 None
Stage IIIC Any size N3 None
Stage IV Any size Any involvement Detectable
N0 = no regional lymph node metastasis
N1 = 1-3 axillary lymph nodes involved and/or internal mammary nodes with metastases detected by biopsy
N2 = 4-9 axillary lymph nodes involved or clinically detected internal mammary nodes in the absence of axillary nodal involvement
N3 = ≤ 10 axillary lymph nodes involved, or infraclavicular lymph nodes, or clinically detected mammary lymph nodes with axillary involvement, or > 3
axillary nodes with internal mammary nodes detected by biopsy, or in ipsilateral supraclavicular lymph nodes
American Joint Committee on Cancer 7th Edition. Breast Cancer Staging.

4. Female Breast Cancer Survival Rates
by Stage of Disease
0
10
20
30
40
50
60
70
80
90
100
0 1 2 3 4 5 6 7 8 9 10
%survival
Years after diagnosis
1National Cancer Database Analytic https://cromwell.facs.org/BMarks/BMCmp/ver10/Docs/#sxs_2008, Assessed September 12, 2011
Graph: West Midlands Cancer Intelligence Unit, 2009. http://info.cancerresearchuk.org/cancerstats/types/breast/survival/#stage. Assessed September 12, 2011.
10-year relative survival
Stage IV (3.7%)
Stage III (8.7%)
Stage II (24.4%)
Stage I (37.7%)
*Additionally, 20.3% of patients in the US are diagnosed as stage 0 and 5.2% are unknown1
Stage (% at dx)*

5. Should All Patients with Newly Diagnosed Breast
Cancer Receive Adjuvant Chemotherapy?
Newly
Diagnosed
Patients
LNs +ve
LNs -ve
Newly
Diagnosed
Patients
Newly
Diagnosed
Patients
LNs +ve
Newly
Diagnosed
Patients
Subsequent Risk of Relapse
Is not Sufficiently Low
•Size.
•Grade.
•ER & PR.
•Her 2 Status.
•Ki 67 Score
Prognosis
Prognostic Calculators
Bonadonna et al. N Engl J Med. 1976;294:405-10
Harris et al. J Clin Oncol. 2007;25:5287-312

6. HR +
HER2 +
Triple Negative
Current Clinical Subtypes in Breast Cancer
10% to 15%2
25% to 30%1 60% to 70%3
1Slamon DJ, et al. New Eng J Med. 2001; 344:783-792; 2Dawood S, et al. J Clin Oncol. 2009;27:220-226; 3 Bedard PL, et al. Breast Cancer Res Treat. 2008;108:307–317.

7. Disease Free Survival and Overall Survival
Rates Based on Clinical Subtype
Disease Free Survival Overall Survival
Onitilo AA, et al. Clinical Medicine & Research. 2009; 7(1/2):4-13

8. Should All Patients with Newly Diagnosed Breast
Cancer Receive Adjuvant Chemotherapy?

9. Surrogate Definitions of Intrinsic Subtypes
Subtype1 Characteristics1 Prognosis2,3,4
Luminal A ER+ and/or PR+
HER2-
Low Ki67
Better prognosis
High survival
Lower recurrence
Luminal B ER+ and/or PR+
HER2+
or HER2- with high Ki67
Poorer prognosis than Luminal A
High survival
HER2 ER- and PR-
HER2+
Poor prognosis
Early and frequent recurrence
Basal-like* Triple negative
ER- and PR-
HER2-
Poor prognosis
Aggressive
1Goldhirsch A, et al. Ann Oncol. 2011;22(8): 1736-1747; 2Carey LA, et al. JAMA. 2006;295(21):2492-2502; 3Calza S, et al. Breast Cancer Res. 266;8(4):R34; 4Dawood S, et al. Breast Cancer Res
Treat. 2011; 126:185-192.
*Approximately 80% overlap between ‘triple negative’ and intrinsic ‘basal-like’ subtype but ‘triple negative’ also includes some
special histological types such as (typical) medullary and adenoid cystic carcinoma with low risks of distant recurrence. Staining for
basal keratins although shown to aid selection of true basal-like tumors, is considered insufficiently reproducible for general use

10. Time to Distant Metastasis and Survival Rates
Based on Molecular Subtype
Sørlie T, et al. PNAS. 2003;100(14):8418-8423.
Time to Distant Metastasis Overall Survival
Luminal A
Luminal B
Basal
HER2+
Censored
p<0.01
N = 97
0
0.2
0.4
0.6
0.8
1.0
Probability
0 24 48 72 96 120
Time to distant metastases (months)
144 168 192
p<0.01
N = 72
0
0.2
0.4
0.6
0.8
1.0
Probability
0 24 48 72 96
Overall survival(months)

11. Should All Patients with Newly Diagnosed Breast
Cancer Receive Adjuvant Chemotherapy?

12. Should All Patients with Newly Diagnosed Breast
Cancer Receive Adjuvant Chemotherapy?

13. Treatment of HR+ Advanced
Breast Cancer

14. Targeted Therapy in Advanced HR+ BC
• The focus of oncology research to specifically inhibit tumor growth
without the damaging side effects of cytotoxic chemotherapy
• Endocrine therapy works by depriving the tumor of estrogen1
– Selective estrogen receptor modulators
• Blocks the effects of estrogen by binding to ER to block estrogen binding
• Includes tamoxifen (Novaldex®), toremifene (Fareston®)
– Selective estrogen receptor down-regulator
• Blocks the effects of estrogen by reducing the number of ER available
• Includes fulvestrant (Faslodex®)
– Aromatase inhibitors
• Inhibits conversion of androgens into estrogen to deprive tumor of estrogen
• Includes anastrozole (Arimidex®), letrozole (Femara®), exemestane
(Aromasin®)
• Recently approved therapies in advanced BC include molecularly-
targeted agents
– HER: Trastuzumab (Herceptin®)2,3,
– VEGF: Bevacizumab (Avastin®)4,
– EGFR/HER: Lapatinib (Tykerb®)5
1Bilynskyj BT. Exp Oncol 2010; 32(3): 190–194; 2Slamon DJ, et al. N Engl J Med 2001;344:783–792; 3Vogel CL, et al. J Clin Oncol 2002; 20:719–726; 4Miller K, et al. N Engl J Med 2007;
357:2666–2676; 5Geyer CE, et al. N Engl J Med 2006;356:2733–2743.

15. HR+ Breast Cancer
• Approximately 75% of invasive breast cancers
(BC) depend on estrogen receptor (ER) and/or
progesterone receptor (PgR) signaling1,2
• ER signaling leads to:
–  cell proliferation rate
–  time available for DNA repair
–  risk of mutation
• Hormone receptor positive (HR+) BCs are
slightly slower growing than HR- cancers1
• Increased HR expression correlates with
improved response to hormonal tx1
– Multiple mechanisms within the HR pathway
allow development of resistance to
antiestrogen treatment3
1Cleator SJ, et al. Clin Breast Cancer 2009;Suppl 1:S6–S17; 2Milani M, et al. Clin Med Ther 2009;1:141–156; 3Arpino G, et al. Endocr Rev. 2008 Apr;29(2):217-33.
Staining of ER+ BC
nuclei by immunohistochemistry (IHC)
A. Strong nuclear staining indicating widespread
expression of HR (Allred score = 8)
B. Weak nuclear staining indicating low–moderate
expression of HR (Allred score = 4)

16. Molecular Biology of ER+ Breast Cancer
ERα Subtype
• Expressed in human breast cancer
• Clinically useful predictive marker
for breast cancer
• Target of treatment regimens in
ER+ breast cancer patients
Arpino G. Endocr. Rev. 2008 29:217-233. Image: Bardin A, et al. Endocrine-Related Cancer 2004; 11:537-551.
ERβ Subtype
• Expressed in human breast cancer
• Its normal function and role in cancer
have not yet been clearly defined
• ERβ may be able to antagonize ERα
• levels may be associated with
resistance to tamoxifen (TAM)
Normal Cells
ERβ
ERα
OH
HO
HO
OH
ERαERβ
Growth
inhibition
Proliferation
Balance?
Tumor Cells
ERβ
ERαOH
HO
HO
OH

17. ER
Baselga J. Oncologist 2011;16:12-19.
Targets of Endocrine Therapy in Hormone Receptor-
Positive Breast Cancer
P
P P
P
P
P
HER2-1
P
PI3-K
SOS
RAS
RAF
Akt P
mTOR
MEK
MAPK
IGFR-1
Plasma
membrane
ER
Cytoplasm
Nucleus
Estrogen
ERE
CBP
ER target gene transcription
p160
Basal
Transcription
machineryER
CBP = CREB binding protein, ER = estrogen receptor, ERE = estrogen-responsive element, HER2 = human epidermal growth factor receptor 2, MAPK = mitogen-activated protein kinase, MEK = mitogen-activated
protein kinase/extracellular signal–related kinase kinase, mTOR = mammalian target of rapamycin, PI3K = phosphoinositide-3 kinase, SOS = son of sevenless
P
P
P
PPP

18. Definitions of Resistance in ER+ Advanced BC
• With initial endocrine treatment in advanced disease, 30% have
objective CR or PR and another 20% have prolonged SD
• Despite the benefits of 5 years of adjuvant tamoxifen3,4
– >50% of women experience BC recurrence
– >2/3 die from their disease after the initial 5 yrs after surgery
• AIs have increased the benefit of adjuvant endocrine treatment5
–  risk of recurrence by 19% (LET v TAM)
–  chance of distant metastases by 27% (LET v TAM)
1Bachelot T, et al. Breast Cancer Res Treat. 2010;100(suppl 1)SABCS 2010:Abstract S1-6; 2Osborne CK, et al. Ann Rev Med. 2011;62:233-247.3Lancet. 1992;339:1–15, 71–8; 4Lancet.
1998;351:1451–67; 5NEJM. 2005; 353: 2747-2757
Primary Resistance1 Secondary Resistance1
Adjuvant Relapse during adjuvant therapy
Metastatic Progression <6 mo of treatment
Response to treatment with
relapse ≥6 mo

19. Phase III: Everolimus + Exemestane in ABC
EVE 10 mg PO daily
+
EXE 25 mg PO daily (n=485)
Placebo PO daily
+
EXE 25 mg PO daily (n=239)
R
Key endpoints
• Primary: PFS (local and central review)
• Secondary: OS, ORR, time to ECOG PS deterioration, safety, change in QOL
2:1
Until disease progression or
unacceptable toxicity
N = 724
• Postmenopausal ER+
• Unresectable locally
advanced or MBC
• Recurrence or progression
after letrozole or
anastrozole
Stratification
• Sensitivity to prior hormone therapy and
visceral metastases
Presented by J. Baselga at the 2011 European Multidisciplinary Cancer Congress (ECCO/ESMO), September 26, 2011. Abstract: 9LBA.

22. Summary
• Endocrine therapy is an integral component of therapy for ER+
BC, but emergence of resistant disease is challenging
• There are multiple pathways of endocrine resistance in BC, both
through de novo and acquired mechanisms
• Despite extensive research, many questions remain on the roles
of the ER, growth factor receptors, and intracellular signaling in
endocrine-therapy resistance
• There is a large unmet need for the treatment of endocrine
therapy-resistant HR+ BC
• Everolimus may represent a paradigm shift in the management
of HR+ ABC

23. Thank You