1. Locally Advanced Breast Cancer
Aspects of ManagementAspects of Management
ByBy
Dr. Farwa ZakirDr. Farwa Zakir

2. Haagensen CD, Stout AP: Carcinoma of the Breast II
- Criteria of Inoperability. Ann Surg 1943, 116: 1032.

3. Criteria of Inoperability
 Bulky axillary diseaseBulky axillary disease
 Skin Manifestations:Skin Manifestations:
 EdemaEdema
 UlcerationUlceration
 Satellite NodulesSatellite Nodules
 FixationFixation
 Chest Wall FixationChest Wall Fixation
 Inflammatory CarcinomaInflammatory Carcinoma
Haagensen CD, Stout AP: Carcinoma of the Breast II - Criteria of Operability. Ann
Surg 1943, 116: 1032.

4. Natural History of Disease
•• Most cases of stage III breast cancer were onceMost cases of stage III breast cancer were once
stage I breast cancerstage I breast cancer
•• In poor countries, more than half of patients haveIn poor countries, more than half of patients have
locally advanced or metastatic disease at the time oflocally advanced or metastatic disease at the time of
diagnosisdiagnosis
–– Lack of educationLack of education
–– Lack of screeningLack of screening

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

6. Clinical Presentation of
Stage III Breast Cancer
Peau d’orange Large mass, edema, and erythema

7. Large primary breast cancer Locally advanced breast cancer
Clinical Presentation of
Stage III Breast Cancer

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

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

10. TNM Staging System for
Advanced Breast Cancer
T3 Tumor >5 cm
T4 Invasion of the chest wall or to the skin (inflammatory )
oT4a Invasion of the chest wall
oT4b Edema, thickening of the skin, or ulceration
of the skin or surrounding skin nodules
oT4c Signs of both T4a and T4b
oT4d Inflammatory cancer (red, swollen, and warm)
Greene FL, et al. AJCC Cancer Staging Manual, 6th ed, 2002.

11. TNM Staging System for
Advanced Breast Cancer
N2 Involvement of four to nine axillary lymph nodes
or of internal mammary lymph nodes without
axillary node involvement.
oN2a Involvement of 4 – 9 axillary lymph nodes
oN2b Involvement of only internal mammary
lymph nodes

12. TNM Staging System for
Advanced Breast Cancer
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
oN3a Involvement of 10 or more axillary lymph
nodes or of the infraclavicular lymph nodes
oN3b Involvement of the internal mammary nodes
and axillary nodes
oN3c Involvement of the supraclavicular nodes

13. 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

14. 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

15. 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.

16. PersonalizingPersonalizing
Treatment to theTreatment to the
Specific TumorSpecific Tumor

17. TNM Stage III Disease
 Tumors > 5 cm with nodesTumors > 5 cm with nodes
 Any tumor with N2/3 nodesAny tumor with N2/3 nodes
 Skin manifestationsSkin manifestations
 Chest wall fixationChest wall fixation
 Inflammatory CarcinomaInflammatory Carcinoma
=> Significant hererogenicity=> Significant hererogenicity
Hermanek P, Sobin LH. TNM classification of malignant tumours. International Union Against CancerHermanek P, Sobin LH. TNM classification of malignant tumours. International Union Against Cancer
1987; 4th Edition Berlin, Springer Verlag:93-9.1987; 4th Edition Berlin, Springer Verlag:93-9.

18. 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

19. TT33 NN11 MM00 TT anyany NN22 MM00
““Can achieve negative path marginsCan achieve negative path margins”” III B & III CIII B & III C
ManagementManagement
OperableOperable Non-operableNon-operable
SurgerySurgery
Then adjuvantThen adjuvant
CTx & RTxCTx & RTx
AccordingAccording
toto
guidelinesguidelines
NeoadjuvantNeoadjuvant
SystemicSystemic
therapytherapy

20. The role of neoadjuvant
chemotherapy
‫ـــــــــــــــــــــــــــــــــــــــــ‬
‫ـــــــــــــــــــــــــــــــ‬AdvantagesAdvantages
 DisadvantagesDisadvantages
 Is it effective ?Is it effective ?
 Indications ?Indications ?
 Which regimen ?Which regimen ?

21. Advantages
‫ـــــــــــــــــــــــــــــــــــــــــــــــــــــــ‬
‫ــــــــــــــــــــــــــــــــــــــــ‬ Early systemic treatmentEarly systemic treatment
 Intact tumor vasculatureIntact tumor vasculature
 In vivo assessment of responseIn vivo assessment of response
 Decrease radical local therapyDecrease radical local therapy
 DownstagingDownstaging
 Increase breast conservationIncrease breast conservation
 Improve resectabilityImprove resectability

22. Disadvantages
‫ـــــــــــــــــــــــــــــــــــــــــــــــــــــــ‬
‫ــــــــــــــــــــــــــــــــــــــــ‬
 Delayed local treatmentDelayed local treatment
 May induce drug resistanceMay induce drug resistance
 Large tumor burdenLarge tumor burden
 Only have clinical stagingOnly have clinical staging
 May increase risk of surgical/XRT complicationsMay increase risk of surgical/XRT complications

23. Is it effective ?
‫ـــــــــــــــــــــــــــــــــــــــــــــــــــــــ‬
‫ــــــــــــــــــــــــــــــــــــــــ‬
 Now achieves a clinical response rate = 60 – 90%.Now achieves a clinical response rate = 60 – 90%.
 Pathological Complete Response rates = 10 - 30 %.Pathological Complete Response rates = 10 - 30 %.
 Improve surgical options; ( ↑ BCS rate)Improve surgical options; ( ↑ BCS rate)
 Compared to adjuvant chemotherapy, the clinicalCompared to adjuvant chemotherapy, the clinical
trials have demonstrated no difference in OS or DFS.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.

24. Indications ?
‫ـــــــــــــــــــــــــــــــــــــــــــــــــــــــ‬
‫ـــــــــــــــــــــــــــــــ‬
 Locally advancedLocally advanced, inoperable breast cancer, inoperable breast cancer
and inflammatory breast cancer.and inflammatory breast cancer.
 Early stageEarly stage, operable breast cancer: improves, operable breast cancer: improves
breast conservation ratesbreast conservation rates

25. Which regimen ?
‫ـــــــــــــــــــــــــــــــــــــــــــــــــــــــ‬
‫ـــــــــــــــــــ‬
Anthracycline Based:Anthracycline Based:
NSABP-B18 EORTCNSABP-B18 EORTC
ACAC FECFEC

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

28. 3 Main Results:
 At 16 years update no diffr. in OS & DFS.⇒At 16 years update no diffr. in OS & DFS.⇒
 The rate of ipsilateral breast cancerThe rate of ipsilateral breast cancer
recurrencerecurrence was slightly higher in thewas slightly higher in the
neoadjuvant groupneoadjuvant group (10.7 versus 7.6 %)(10.7 versus 7.6 %),,
especially among younger patients (age ≤50especially among younger patients (age ≤50
years).years).
 Statistically significant correlation betweenStatistically significant correlation between
primary tumor response and outcome.primary tumor response and outcome.

29. Overall survival and response
to chemotherapy
5- years survival5- years survival::
Path CR = 87%Path CR = 87%
Clin PR = 68%Clin PR = 68%
Clin NR = 64%Clin NR = 64%
p<0.0001p<0.0001
0 1 2 3 4 5
50
60
70
80
90
100
path CR
clin PR
clin NR
years
distantdisease-free
survival(%)

30. What is the Place of Surgery?
 ““Intensive chemotherapy can restore the majority ofIntensive chemotherapy can restore the majority of
patients to “no evidence of disease”patients to “no evidence of disease”Booser D,. Semin.Oncol.1992;19(3):278-85.Booser D,. Semin.Oncol.1992;19(3):278-85.
 But:But:
 Complex, expensive regimens employedComplex, expensive regimens employed
 Pathologic complete responses <10%Pathologic complete responses <10%
 + Radiotherapy: Pathologic complete responses still <20%+ Radiotherapy: Pathologic complete responses still <20% Shanta VShanta V
et al: BC. Clin Oncol 1991;3(3):137-40et al: BC. Clin Oncol 1991;3(3):137-40..
 => Local control improved by surgery=> Local control improved by surgery andand radiotherapyradiotherapy
Toonkel LM et al, Int.J Radiat.Oncol.Biol.Phys. 1986;12(9):1583-7.Toonkel LM et al, Int.J Radiat.Oncol.Biol.Phys. 1986;12(9):1583-7.

31. Sequencing I:
Radiotherapy and Surgery
 Radiotherapy followed by surgery:Radiotherapy followed by surgery:
 25% wound infection25% wound infection
 34% delayed healing34% delayed healing
 63% seroma63% seroma
 22% lymphoedema22% lymphoedema (Badr-el-Din et al: Local postoperative morbidity following pre-operative irradiation in LABC.(Badr-el-Din et al: Local postoperative morbidity following pre-operative irradiation in LABC.
Eur J Surg Oncol. 1989;15(6):486-9.)Eur J Surg Oncol. 1989;15(6):486-9.)
 => Prefer Surgery followed by RT=> Prefer Surgery followed by RT

32. Sequencing II:
Chemotherapy and Surgery
 Complications not increased with anthracyclins norComplications not increased with anthracyclins nor
taxanestaxanes(Broadwater JR et al. Ann Surg 1991;213(2):126-9).(Broadwater JR et al. Ann Surg 1991;213(2):126-9).
 Oncologic outcome not affectedOncologic outcome not affected (Cunningham JD et al. Cancer Invest. 1998;16(2):80-6).(Cunningham JD et al. Cancer Invest. 1998;16(2):80-6).
 => Prefer preop. chemotherapy=> Prefer preop. chemotherapy

33. Breast Reconstruction
 Added morbidity minimalAdded morbidity minimal
 Avoid ProsthesesAvoid Prostheses (Sultan MR et al. Ann Plast Surg 1997;38(4):345-9).(Sultan MR et al. Ann Plast Surg 1997;38(4):345-9).

34. Conclusions
 Surgery essential part of therapySurgery essential part of therapy
 Challenges:Challenges:
Breast ConservationBreast Conservation
Breast ReconstructionBreast Reconstruction
Selective Management of the AxillaSelective Management of the Axilla
Increasing AwarenessIncreasing Awareness

35. Thank You