Locally Advanced Breast Cancer

Aspects of ManagementAspects of Management

ByBy

Dr. Farwa ZakirDr. Farwa Zakir

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

Criteria of Inoperability Bulky axillary disease Bulky 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.

Natural History of Disease

• • Most cases of stage III breast cancer were once Most cases of stage III breast cancer were once stage I breast cancerstage I breast cancer

•• In poor countries, more than half of patients have In poor countries, more than half of patients have

locally advanced or metastatic disease at the time of locally advanced or metastatic disease at the time of diagnosisdiagnosis

– – Lack of educationLack of education – – Lack of screeningLack of screening

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

Clinical Presentation ofStage III Breast Cancer

Peau d’orange Large mass, edema, and erythema

Large primary breast cancer Locally advanced breast cancer

Clinical Presentation ofStage III Breast Cancer

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

Breast Cancer Up Until Now:Testing for 1 or 2 Specific Molecules

Estrogen Receptor: 75% of Estrogen Receptor: 75% of breast cancers are ER+breast cancers are ER+

HER-2: 20-25% of breast HER-2: 20-25% of breast cancers are HER-2+cancers are HER-2+

TNM Staging System forAdvanced 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.

TNM Staging System forAdvanced 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

TNM Staging System forAdvanced 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

Stage Classifications for LocallyAdvanced 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

Stage Classifications for LocallyAdvanced 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

Survival According to Treatment

TreatmentNo. of

Patients5-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.

Personalizing Personalizing Treatment to the Treatment to the Specific TumorSpecific Tumor

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 Cancer Hermanek 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.

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

TT33 N N11 M M00 T T anyany N N22 M M00

““Can achieve negative path marginsCan achieve negative path margins”” III B & III C III B & III C

ManagementManagement

OperableOperable Non-operableNon-operable

SurgerySurgery Then adjuvantThen adjuvant

CTx & RTxCTx & RTxAccordingAccording

to to guidelinesguidelines

NeoadjuvantNeoadjuvantSystemicSystemictherapytherapy

The role of neoadjuvant chemotherapyـ ـ ـ ـ ـ ـ ـ ـ ـ ـ ـ ـ ـ ـ ـ ـ ـ ـ ـ ـ ـ ـ ـ ـ ـ ـ ـ ـ ـ ـ ـ ـ ـ ـ ـ ـ ـ ـ ـ ـ ــ ـ ـ ـ ـ ـ ـ ـ ـ ـ ـ ـ ـ ـ ـ ـ ـ ـ ـ ـ ـ ـ ـ ـ ـ ـ ـ ـ ـ ـ AdvantagesAdvantagesـ

DisadvantagesDisadvantages Is it effective ?Is it effective ? Indications ?Indications ? Which regimen ?Which regimen ?

Advantages ــــ ـــــ ـــــ ـــــ ـــــ ـــــ ـــــ ـــــ ـــــ ـــــ ـــــ ـــــ ـــــ ـــــ ـــــ ـــــ ـــــ ـــــ ـــــ ـ

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

Disadvantages ــــ ـــــ ـــــ ـــــ ـــــ ـــــ ـــــ ـــــ ـــــ ـــــ ـــــ ـــــ ـــــ ـــــ ـــــ ـــــ ـــــ ـــــ ـــــ ـ

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

Is it effective ?ــــ ـــــ ـــــ ـــــ ـــــ ـــــ ـــــ ـــــ ـــــ ـــــ ـــــ ـــــ ـــــ ـــــ ـــــ ـــــ ـــــ ـــــ ـــــ ـ

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 clinical Compared 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.

Indications ?ــــ ـــــ ـــــ ـــــ ـــــ ـــــ ـــــ ـــــ ـــــ ـــــ ـــــ ــــــ ـــــ ـــــ ـــــ ـــــ ـــــ ـ

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 rates breast conservation rates

Which regimen ?ــــ ـــــ ـــــ ـــــ ـــــ ـــــ ـــــ ـــــ ـــــ ـــــ ـــــ ــــ ـــــ ـــــ ـــــ ـ

Anthracycline Based:Anthracycline Based:

NSABP-B18 EORTCNSABP-B18 EORTC

ACAC FECFEC

NSABP-B18(2001 updated JCO, 2008)⇒

$ 4 X AC⇒$ 4 X AC⇒

4 X AC $⇒4 X AC $⇒

1523 pts.

T1-3N0-1

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 cancer The rate of ipsilateral breast cancer recurrencerecurrence was slightly higher in the was slightly higher in the neoadjuvant group neoadjuvant group (10.7 versus 7.6 %)(10.7 versus 7.6 %),, especially among younger patients (age ≤50 especially among younger patients (age ≤50 years).years).

Statistically significant correlation between Statistically significant correlation between primary tumor response and outcome.primary tumor response and outcome.

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 4 550

60

70

80

90

100

path CR

clin PRclin NR

years

dis

tan

t d

isea

se-f

ree

surv

ival

(%

)

What is the Place of Surgery? ““Intensive chemotherapy can restore the majority of Intensive 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 employed Complex, expensive regimens employed

Pathologic complete responses <10%Pathologic complete responses <10%

+ Radiotherapy: Pathologic complete responses still <20% + Radiotherapy: Pathologic complete responses still <20% Shanta V Shanta 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 and and radiotherapy radiotherapy

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.

Sequencing I: Radiotherapy and Surgery

Radiotherapy followed by surgery:Radiotherapy followed by surgery:

25% wound infection 25% wound infection

34% delayed healing 34% delayed healing

63% seroma63% seroma

22% lymphoedema 22% 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

Sequencing II: Chemotherapy and Surgery

Complications not increased with anthracyclins nor Complications 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 affected Oncologic 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

Breast Reconstruction

Added morbidity minimal Added morbidity minimal

Avoid Prostheses Avoid 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).

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

Thank You