1. Locally advanced breast cancer
to be easily digested….!
By
Osama El-Zaafarany

2. 
Approximately 20 to 25% of women present
with locally advanced cancer.

Inflammatory breast cancer represents 1 to 3%
of diagnosed breast cancers.

Long-term survival can be obtained in
approximately 50 % of women with locally
advanced breast cancer who are treated with a
multimodality approach.
5-year relative survival rates for patients presenting
with stage IIIA ⇒ 52 % and stage IIIB ⇒ 48 %

3. locally advanced breast cancer includes patients
with stage III disease, this comprises:
 Advanced primary tumors:
•
•
•
(T3): Tumors > 5 cm in greatest dimension.
(T4): Direct extension to the chest wall and/or to the skin.
Inflammatory breast cancer.
 Advanced regional lymph nodes:
•
(N2): Ipsilateral level I, II axillary lymph nodes that are clinically fixed
or matted or clinically detected internal mammary lymph nodes in the
absence of axillary lymph node metastases.
•
(N3): Ipsilateral infraclavicular (level III axillary) lymph nodes,
ipsilateral internal mammary lymph node(s) with axillary lymph nodes, or
ipsilateral supraclavicular lymph nodes.

4. work up updates
NCCN 2013 guidelines
 Breast MRI, bone scan. (category 2B).
 Abdominal imaging with diagnostic CT (without
pelvic CT) or MRI (category 2A) are optional unless
directed symptoms or other abnormal study results.
 PET/CT scan is also included as an optional
additional study (category 2B), The consensus of the
Panel is that FDG PET/CT is most helpful in
situations where standard imaging results are equivocal
or suspicious.
‫ــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــ‬
Category 2: based on lower-level evidence.

5. Management
Operable
T3 N1 M0
“Can achieve negative path margins”
Surgery
Then adjuvant
CTx & RTx
According
to
guidelines
Non-operable
T any N2 M0
III B & III C
Neoadjuvant
Systemic
therapy

6. The role of neoadjuvant
chemotherapy
‫ــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــ‬
• Is it effective ?
•
•
•
Indications ?
Which regimen ?
Number of cycles ?

7. Is it effective ?
‫ــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــ‬
•
•
•
•
Now achieves a clinical response rate = 60 – 90%.
Path CR rates = 10 - 30 %.
Improve surgical options; ( ↑ BCS rate)
Compared to adjuvant chemotherapy, the clinical
trials have demonstrated no difference in OS or DFS.
Guarneri V, Frassoldati A, Giovannelli S, et al. Primary systemic therapy for operable breast cancer: a review of
clinical trials and perspectives. Cancer Lett 2007; 248:175.

8. Indications ?
‫ــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــ‬
• Locally advanced, inoperable breast cancer and
inflammatory breast cancer.
• Early stage, operable breast cancer: improves
breast conservation rates

9. ‫? ‪Which regimen‬‬
‫ــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــ‬
‫:‪Anthracycline Based‬‬
‫‪FEC‬‬
‫‪AC‬‬
‫‪EORTC‬‬
‫81‪NSABP-B‬‬

10. NSABP-B18
(2001⇒ updated JCO, 2008)
1523 pts.
$ ⇒ 4 X AC
T1-3
N0-1
4 X AC ⇒ $

12. 3 Main Results:
• At 16 years update ⇒ no diffr. in OS & DFS.
• The rate of ipsilateral breast cancer recurrence
was slightly higher in the neoadjuvant group
(10.7 versus 7.6 %), especially among younger
patients (age ≤50 years).
• Statistically significant correlation between
primary tumor response and outcome.

13. Overall survival and response to chemotherapy
distant disease-free
survival (%)
100
5- years survival:
90
Path CR = 87%
Clin PR = 68%
Clin NR = 64%
80
70
path CR
clin NR
clin PR
60
50
0
1
2
3
4
years
p<0.0001
5

14. EORTC
( JCO, 2001)
Neo-adjuv FEC.
698 pts.
T1c-T4b
Adjuv FEC.
Median FU=65 ms⇒ no diffr in 4-ys OS, PFS, LRR

15. Taxanes:
Adding Taxanes to Anthracycline-based ⇒
•
•
Increases response rates in the preoperative setting.
Not establish a survival benefit.
AC→D
AC→D
NSABP-B27
GEPARDUO

16. NSABP-B27
2411 pts
(JCO 2003, updated 2006)
T1c-3/N0
T1-3/N1
Docetaxel ↑ pCR
Pts with pCR ⇒ ↑ OS, DFS
D ⇒ ↑ BCS (63% vs 61%)
8-ys update:
No diffr in OS
and DFS.

18. GEPARDUO
( JCO, 2005 )
Investigate
Sequential
VS
Combined
Dose
dense
Anthracycline
& Taxanes
Sequential
is superior
Inferior

19. GEPARDUO
( JCO, 2005 )
AD + G-CSF
every 14 day
913 pts
T  2 cm
(stage I,II)
Adriamycin
Taxotere
Adriamycin
Cyclophosphamide
Taxotere
Dose dense,
Combined arm
AC→D
/21 days
Sequential
arm
von Minckwitz et al., J Clin Oncol 1999
von Minckwitz et al., J Clin Oncol 2001

20. pCR
30%
P < 0.001
20%
16.1%
22.4%
10%
7.7%
11.5%
0
3.8%
AD
6.3%
AC  Taxotere
In situ residuals only

21. Dose-dense:
2 trials:
GEPARDUO.
Multicenter Trial.
(EORTC-NCIC-SAKK, JCO, 2003)
dose-dense FEC vs FEC-21
Dose dense
was inferior
no diffr in pCR, PFS, OS

22. Xeloda ⇒ 2 Trials
GEPARTRIO,
2008
4 X TAC
4 X TAC ⇒ no response
4 x Navelbine + Xeloda
no diffr in pCR

23. GEPARQUATRO: JCO, 2010
RAND
4 x EC → D (+Herceptin 1y)
4 x D + Xeloda (+Herceptin)
4 x D →Xeloda (+Herceptin)
Xeloda failed to improve pCR
Higher pCR in Her2 +ve pts:
(31.7 % vs 15.7%)

24. Herceptin:
With Chemo.
NOAH
Trial
GeparQuattro
With other
targeted agents
Lapatinib
NeoAltto
Trial
+
GERPARQUINTO
Pertuzumab
NeoSphere
Phase II
trial

25. NOAH
Neoadjuvant Herceptin Trial
Lancet, 2010
3 x Paclitaxel-Adria →3 x Paclitaxel→ 4 x CMF
228 pts
Local adv
Her2 +ve
Same chemo + Herceptin and continue H. for
1 year ⇒
↑pCR (43 vs 23 %)
↑ 3-ys EFS (71 vs 56%)

26. Neo-ALTTO
Lancet, 2012

27. Hercpt + Lapt.
Chemo +
↑ pCR (51.3%)
↑ G3/4 liver enz abn.
Hercpt. ⇒ pCR= 29.5%
Lapat. ⇒ pCR = 24.7 %

30. GEPARQUINTO
Lancet, 2012
With Herceptin ⇒ pCR:30.3%
620 pts.
Her2 +ve
EC → D
With Lapatinib ⇒ pCR:22.7%

31. NeoSphere
Presented San-Antonio 2011.
Phase II trial.
trastuzumab + pertuzumab +docetaxel
resulted in
significantly higher pCR ⇒(45.8%)
Compared to
trastuzumab/docetaxel ⇒ 29 %
pertuzumab/docetaxel ⇒ 17.8 %
trastuzumab/pertuzumab alone ⇒ 24.0 %

32. Neoadjuvant
CTx vs HTx
Phase II study: (Cancer, 2007)
Exemestane
or Anastrazole
⇒ 3 ms
Overall clinical resp
= 67% &62%
pCR = 3 %
4 x Taxol-Adria
/21ds
Overall clinical resp =
63 %
pCR = 6 %
121 pts
postmenop
No diffr.

33. GEICAM study
Spanish Breast Cancer Research Group
JCO, 2010
4 x EC→4 x D
No Differ.
In overall clin resp
Or pCR
Multicenter
Phase II
Exemestane
(+Zoladex in premenop)
24 Ws

34. Tam vs AIs
Letrozole
Exemestane
Anastrazole
Phase III
Po24 trial
2007
JCO, 2005
IMPACT
JCO, 2005
Significant higher
Overall clin object resp
BCS rate
With Letrezole
PROACT
Cancer, 2006
No differ.
Significant higher
Overall clin object resp
BCS rate
With Exemest.

35. Po24 trial

36. Anastrozole Vs Letrozole Vs Exemestane
A preliminary report of the American College of
Surgeons Oncology Group (ACOSOG) Z1031
trial (phase II, JCO, 2010) confirmed equivalent
efficacy between these agents and reinforced
the antitumor efficacy of neoadjuvant aromatase
inhibitor therapy.

37. Hormonal + Targeted
lapatinib, has been tested as neoadjuvant
therapy in combination with letrozole:
• LET-Lob, phase II study, JCO, 2009.
• 39 patients , completed six months .
• objective response rate of 50 %, a clinical
complete response rate of 9 %, and no
confirmed pathologic complete responses