Locally advanced breast cancer
to be easily digested….!

By
Osama El-Zaafarany


Approximately 20 to 25% of women present
with locally advanced cancer.



Inflammatory breast cancer represents 1 to 3...
locally advanced breast cancer includes patients
with stage III disease, this comprises:
 Advanced primary tumors:
•
•
•
...
work up updates
NCCN 2013 guidelines

 Breast MRI, bone scan. (category 2B).
 Abdominal imaging with diagnostic CT (with...
Management
Operable

T3 N1 M0

“Can achieve negative path margins”

Surgery

Then adjuvant
CTx & RTx
According
to
guidelin...
The role of neoadjuvant
chemotherapy
‫ــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــ‬
• Is it ef...
Is it effective ?
‫ــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــ‬
•

•
...
Indications ?
‫ــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــ‬
• Locally advanced,...
‫? ‪Which regimen‬‬
‫ــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــ‬
‫:‪Anthracycline Based‬‬
...
NSABP-B18
(2001⇒ updated JCO, 2008)

1523 pts.

$ ⇒ 4 X AC

T1-3
N0-1

4 X AC ⇒ $
3 Main Results:
• At 16 years update ⇒ no diffr. in OS & DFS.

• The rate of ipsilateral breast cancer recurrence
was slig...
Overall survival and response to chemotherapy

distant disease-free
survival (%)

100

5- years survival:

90

Path CR = 8...
EORTC
( JCO, 2001)

Neo-adjuv FEC.
698 pts.
T1c-T4b

Adjuv FEC.
Median FU=65 ms⇒ no diffr in 4-ys OS, PFS, LRR
Taxanes:
Adding Taxanes to Anthracycline-based ⇒
•
•

Increases response rates in the preoperative setting.
Not establish ...
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...
GEPARDUO
( JCO, 2005 )

Investigate

Sequential
VS

Combined

Dose
dense

Anthracycline
& Taxanes

Sequential
is superior
...
GEPARDUO
( JCO, 2005 )

AD + G-CSF
every 14 day

913 pts
T  2 cm
(stage I,II)
Adriamycin
Taxotere
Adriamycin
Cyclophospha...
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
Dose-dense:
2 trials:
GEPARDUO.

Multicenter Trial.
(EORTC-NCIC-SAKK, JCO, 2003)

dose-dense FEC vs FEC-21
Dose dense
was ...
Xeloda ⇒ 2 Trials
GEPARTRIO,

2008

4 X TAC

4 X TAC ⇒ no response
4 x Navelbine + Xeloda

no diffr in pCR
GEPARQUATRO: JCO, 2010

RAND

4 x EC → D (+Herceptin 1y)
4 x D + Xeloda (+Herceptin)
4 x D →Xeloda (+Herceptin)
Xeloda fai...
Herceptin:
With Chemo.

NOAH
Trial

GeparQuattro

With other
targeted agents

Lapatinib

NeoAltto
Trial
+
GERPARQUINTO

Pe...
NOAH
Neoadjuvant Herceptin Trial
Lancet, 2010

3 x Paclitaxel-Adria →3 x Paclitaxel→ 4 x CMF

228 pts
Local adv
Her2 +ve

...
Neo-ALTTO
Lancet, 2012
Hercpt + Lapt.

Chemo +

↑ pCR (51.3%)
↑ G3/4 liver enz abn.

Hercpt. ⇒ pCR= 29.5%
Lapat. ⇒ pCR = 24.7 %
GEPARQUINTO
Lancet, 2012

With Herceptin ⇒ pCR:30.3%
620 pts.
Her2 +ve

EC → D

With Lapatinib ⇒ pCR:22.7%
NeoSphere
Presented San-Antonio 2011.
Phase II trial.
trastuzumab + pertuzumab +docetaxel
resulted in
significantly higher...
Neoadjuvant
CTx vs HTx
Phase II study: (Cancer, 2007)
Exemestane
or Anastrazole
⇒ 3 ms

Overall clinical resp
= 67% &62%
p...
GEICAM study
Spanish Breast Cancer Research Group
JCO, 2010

4 x EC→4 x D
No Differ.
In overall clin resp
Or pCR

Multicen...
Tam vs AIs
Letrozole

Exemestane
Anastrazole
Phase III

Po24 trial
2007

JCO, 2005

IMPACT
JCO, 2005

Significant higher
O...
Po24 trial
Anastrozole Vs Letrozole Vs Exemestane
A preliminary report of the American College of
Surgeons Oncology Group (ACOSOG) Z1...
Hormonal + Targeted
lapatinib, has been tested as neoadjuvant
therapy in combination with letrozole:
• LET-Lob, phase II s...
Locally advanced breast cancer
Locally advanced breast cancer
Locally advanced breast cancer
Locally advanced breast cancer
Locally advanced breast cancer
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Locally advanced breast cancer

  1. 1. Locally advanced breast cancer to be easily digested….! By Osama El-Zaafarany
  2. 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. 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. 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. 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. 6. The role of neoadjuvant chemotherapy ‫ــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــ‬ • Is it effective ? • • • Indications ? Which regimen ? Number of cycles ?
  7. 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. 8. Indications ? ‫ــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــ‬ • Locally advanced, inoperable breast cancer and inflammatory breast cancer. • Early stage, operable breast cancer: improves breast conservation rates
  9. 9. ‫? ‪Which regimen‬‬ ‫ــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــ‬ ‫:‪Anthracycline Based‬‬ ‫‪FEC‬‬ ‫‪AC‬‬ ‫‪EORTC‬‬ ‫81‪NSABP-B‬‬
  10. 10. NSABP-B18 (2001⇒ updated JCO, 2008) 1523 pts. $ ⇒ 4 X AC T1-3 N0-1 4 X AC ⇒ $
  11. 11. 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.
  12. 12. 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
  13. 13. EORTC ( JCO, 2001) Neo-adjuv FEC. 698 pts. T1c-T4b Adjuv FEC. Median FU=65 ms⇒ no diffr in 4-ys OS, PFS, LRR
  14. 14. 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
  15. 15. 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.
  16. 16. GEPARDUO ( JCO, 2005 ) Investigate Sequential VS Combined Dose dense Anthracycline & Taxanes Sequential is superior Inferior
  17. 17. 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
  18. 18. 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
  19. 19. 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
  20. 20. Xeloda ⇒ 2 Trials GEPARTRIO, 2008 4 X TAC 4 X TAC ⇒ no response 4 x Navelbine + Xeloda no diffr in pCR
  21. 21. 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%)
  22. 22. Herceptin: With Chemo. NOAH Trial GeparQuattro With other targeted agents Lapatinib NeoAltto Trial + GERPARQUINTO Pertuzumab NeoSphere Phase II trial
  23. 23. 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%)
  24. 24. Neo-ALTTO Lancet, 2012
  25. 25. Hercpt + Lapt. Chemo + ↑ pCR (51.3%) ↑ G3/4 liver enz abn. Hercpt. ⇒ pCR= 29.5% Lapat. ⇒ pCR = 24.7 %
  26. 26. GEPARQUINTO Lancet, 2012 With Herceptin ⇒ pCR:30.3% 620 pts. Her2 +ve EC → D With Lapatinib ⇒ pCR:22.7%
  27. 27. 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 %
  28. 28. 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.
  29. 29. 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
  30. 30. 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.
  31. 31. Po24 trial
  32. 32. 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.
  33. 33. 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
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