Adjuvant treatment in early and localy advanced breast cancer

Adjuvant Treatment in

Early & Locally Advanced Breast Cancer

Prof. (R) Dr. Syed Ijaz Hussain Shah

Sahil Hospital Faisalabad

Age-standardised cancer incidence and mortality

GLOBOCAN 2008 (LARC) (5.10.2012).

International agency for research on cancer

800000 600000 400000 200000 0 200000 400000 600000 800000

Breast

LungCervix uteri

Colorectal

StomachCorpus uteri

LiverOvary

ThyroidNon-Hodgkin lymphoma

Women, all ages (N)

Less developed regionsMore developed regions

Incidence Mortality

Over view of Breast cancerMost common cancer in humanity

Effective Screening available

Early detection-good prognosis

Curable disease

Even in Advanced stages

Good palliation for metastatic pt.

Early Breast CancerIntroductionPresentationDiagnosisStagingTreatmentEBC-----------T1/2, N0/1, M0LABC---------T3/4, N2/3, M0/1MBC----------any TNM distant metsIndication of adjuvant treatmentChemotherapyRadiation therapyHormone therapyTarget therapy-Trastuzumab36% RRR40% Decrease in death

Surgery ------------ Diagnostic/BCS/MRM

Chemotherapy for selective patients

Radiotherapy for selective patients

Hormone replacement therapy for

HORMONE POSITIVE PATIENTS

BIOLOGICAL therapy for

HER2/neu over expression patients

Early Breast CancerEBC-----------T1/2, N0/1, M0

SURGERY

LUMPECTOMY

WIDE LOCAL EXCISION

QUARDERANTECTOMY

SIMPLE MASTECTOMY

MODIFIED RADICAL MASTECTOMY

Adjuvant Treatment for EBC

• Chemotherapy:• CMF/AC/EC• Taxanes/Capcitabine/Gemcitabine• Hormone Therapy for ---------selected patients• 1--AntiEstrogen • 2--Aromatase inhibitor for Postmenopausal

patients • Radiation Therapy for selected patients

What is HER Family

Humam Epidermal Growth Factor Receptor HER1HER2HER3HER4Only HER2 is significant in Tumor AntigenIts percentage of positivity in Breast cancervaries from 14 ----26.It is associated with poor prognosis and early recurrence

Identifying the right patient: HER2 testing

• High-quality HER2 testing is essential to ensure optimal identification of patients with HER2-positive tumours eligible for HER2-targeted therapy

• There are several HER2 testing methods currently used to detect HER2 protein or gene amplification

– IHC, FISH, CISH, SISH, dual SISH

• With all methodologies, it is essential that all tests are standardised and validated within each laboratory

Penault-Llorca F, et al. The Breast 2013; 22:200–202; Wolff AC, et al. J Clin Oncol 2013 (Epub ahead of print).

HER2 overexpression / amplification occurs frequently in breast cancer

Study n Stage HER2 positive, %

Acosta 2001

Ross 2003

Owens 2004a

Press 2005b

Francis 2007

Gown 2008a

Ferno 2007

Penault-Llorca 2008

UK NEQAS 2007

9307

5227

16,092

2502

6512

6604

5043

2079

30,720

I-IV

I-III

I-IV

I-IV

NS

NS

NS

I-III

I-IV

20

24

23

26

17

20

14

16

15

aData from high-throughput laboratories; bBCIRG reference laboratoryEBC, early breast cancer; IHC, immunohistochemistry; FISH, fluorescence in situ hybridisation; NS, not specified; NEQAS, National External Quality Assessment Scheme; BCIRG, Breast Cancer International Research Group

Method

IHC / FISH

NS

FISH only

FISH only

IHC

IHC / FISH

IHC / FISH

IHC / FISH

FISH

HER2-positivity rates in Breast Cancer

Overexpression of HER2 is associated with poor prognosis

Pauletti et al 2000

Probabilityof survival (%)

Time (months)0 12 60 96 120

100

90

80

70

60

50

4024 36 48 72 84 108

Log-rank p=0.0004Wilcoxon p=0.0009

EBC patientsa

HER2 negative (n=771)HER2 positive (n=189)

aUnselected stage I, II and III breast cancer patients

Breast cancer HER2 testing algorithm

If primary ISH testing is used, patients whose tumours overexpress the HER2 protein (i.e. IHC 3+) may not always be identified.Hanna W & Kwok K. Mod Pathol 2006; 19:481–487.

IHC ISH(FISH or CISH)

0 3+2+1+

– +Retest with ISH(FISH, CISH,

SISH)

– +

Eligible forHER2-targeted

therapy

Eligible forHER2-targeted

therapy

Eligible for HER2-targeted

therapy

Patient tumour sample

ASCO/CAP guidelines for HER2 testing*

• An update to the ASCO/CAP guidelines for HER2 testing was published online on 7 October 2013

• All primary breast cancer specimens and metastases should have at least one HER2 test performed:

• All newly diagnosed patients with breast cancer must have a HER2 test performed

• Patients who then develop metastatic disease must have a HER2 test performed in a metastatic site, if tissue sample

is available

• This should be especially considered for a patient who previously tested HER2-negative in a primary tumour and presents with disease recurrence with clinical behaviour suggestive of HER2-positive or triple-negative disease

* Please note: International guidelines may not be in line with current national guidelines. ASCO/CAP, American Society of Clinical Oncology/College of American Pathologists.Wolff AC, et al. J Clin Oncol 2013 (Epub ahead of print).

Biology of HER2 and its importance in breast cancer

Trastuzumab: targeting HER2

Recombinant humanised monoclonal antibody directed against the extracellular domain of HER2

Attacks HER2-positive tumours via 4 distinct mechanisms of action

1. Activation of antibody-dependent cellular cytotoxicity (ADCC)

2. Prevention of the formation of p95HER2, a truncated and very active form of HER2

3. Inhibition of cell proliferation by preventing HER2-activated intracellular signalling

4. Inhibition of HER2-regulated angiogenesis

3

HER2/neu targeted Therapy(Trastuzumab)

1=1 year of Herceptin (Trastuzumab) if added to therapy increased the chance of remaining cancer free longer1

2=After completion of chemotherapy Weekly Trastuzumab with Taxane for 12

weeks followed by Herceptin alone weekly 3= 52% higher chance of remaining cancer free

longer in the group of women who received

AC→TH compared with the group that received AC→T

continusurgery and chemotherapy, Herceptin taken every 3 weeks

46% higher chance of remaining cancer free longer who received Herceptin alone compared with that did not receive

2% of patients on AC→TH experienced congestive heart failure (CHF) vs 0.4% without Herceptin

contin

36 % Reduction in Risk of Relapse

40 % decrease in death rate

Comparison

Observation for HER2/neu +

Three months /one year

One year/ two years

Trastuzumab/ lapatinib

Trastuzumab plus lapatinib

Joint Analysis of NSABP B-31 and NCCTG N9831

Trastuzumab plus adjuvant chemotherapy for HER2-positive breast cancer: final planned joint analysis of overall survival from NSABP B-31 and NCCTG N9831

Joint Analysis of NSABP B-31 and NCCTG N9831

OS with 1 Years of Herceptin versus observation

Goldhirsch A et al. Proc SABCS 2012;Abstract S5-2.

Conclusion

Results of the HERA study at 8 years of median follow-up show sustained and statistically significant DFS and OS benefit for 1 year of trastuzumab versus observation in analyses despite selective crossover.

1 year of trastuzumab remains a standard part of adjuvant therapy for patients with HER2-positive early BC.

Benefit for 1 year of trastuzumab, compared to observation, was ---Early recurrence ,more events and less DFS in observational arm.

Goldhirsch A et al. Proc SABCS 2012;Abstract S5-2.

Locally AdvancedPrimary Breast Cancer

Natural History of Disease

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

In poor countries, more than half of patients have locally advanced or metastatic disease at the time of diagnosis

Lack of education Lack of screening

Clinical Presentation

“Grave clinical signs” – Skin ulceration – Skin edema – Tumor fixation to the chest wall – Axillary nodes larger than 2.5 cm – Fixed axillary nodes •Satellite skin nodules and infraclavicular, internal mammary, and supraclavicular adenopathy

Clinical Presentation Stage III BreastCancer

Peau d’orange Large mass, edema, and erythema

Clinical Presentation of Stage III, LocallyAdvanced (Inoperable) Disease

Large primary breast cancer Locally advanced breast cancer

Diagnostic Work-Up •Distinguish benign from malignant disease

•Distinguish noninvasive from invasive disease

• Obtain pathologic diagnosis before treatment:

– Percutaneous image-guided biopsy (preferred)

-Core-needle biopsy-Fine-needle aspiration

- Excisional 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 cmT4 Invasion of the chest wall or to the skin (inflammatory breast cancer) T4a Invasion of the chest wall T4b Edema, thickening of the skin, or ulceration of the skin or surrounding skin nodules T4c Signs of both T4a and T4b T4d Inflammatory cancer (breast is red, swollen, and warm)Greene FL, et al. AJCC Cancer Staging Manual, 6th ed, 2002.

TNM Staging System forAdvanced Breast Cancer (cont.)

N2 Involvement of four to nine axillary lymph nodes or of internal mammary lymph nodes without axillary node involvement.

N2a Involvement of four to nine axillary lymph nodes N2b Involvement of only internal mammary lymph nodes

TNM Staging System forAdvanced Breast Cancer (cont.)

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 N3a Involvement of 10 or more axillary lymph nodes or of the infraclavicular lymph nodes N3b Involvement of the internal mammary nodes and axillary nodes N3c Involvement of the supraclavicular nodes

Stage Classifications for Locally

Advanced Breast Cancer

Stage IIB T2 N1 M0

T3 N0 M0Stage IIIA T0 N2 M0

T1 N2 M0T2 N2 M0T3 N1 M0T3 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

Multidisciplinary Cancer Breast Management

Survival According to TreatmentTreatment No. 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 Treatment to Personalizing Treatment to the Specific Tumorthe Specific Tumor

Multidisciplinary Cancer Breast Management Multidisciplinary Cancer Breast Management


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


Chemotherapy for Breast Cancer

•Improves disease-free and overall survival•Anthracycline-based combinations are better than combination of cyclophosphamide, methotrexate, and fluorauracil (CMF)•Taxane-based combinations are more effective in the adjuvant setting•Trastuzumab in the adjuvant setting improves disease-free and overall survival


Neoadjuvant Chemotherapy (cont.)

•Goals:– Decrease tumor size– Minimize surgery– Establish tumor sensitivity

•Appropriate treatments:– Chemotherapy– Tamoxifen or aromatase inhibitors– Radiation therapy


Clinical Rationale for Preoperative Chemotherapy

•Excellent response rates for locally advanced breast cancer• Efficacy of adjuvant chemotherapy for node- negative breast cancer• Equivalent survival for breast-conserving surgery and mastectomy


Advantages ofNeoadjuvant Chemotherapy

•Increased rate of breast-conserving surgery•Earlier treatment of micrometastases•Treatment serves as in vivo chemosensitivity assay•Improved rates of local control and disease-free survival


Factors Influencing Decision to UseNeoadjuvant Chemotherapy in Operable

Breast Cancer•Does the patient need adjuvant chemotherapy based on information known prior to surgery?•Would neoadjuvant chemotherapy potentially alter the extent of resection?•Does the patient desire breast preservation?•Would treatment benefit from knowledge of in vivo chemosensitivity?

NSABP B-18 Trial: Schema

OperableOperable BreastBreast CancerCancer

•Stratification•• Age•• Clinical tumor size•• Clinical node status

OperationOperation AC x 4AC x 4++ TAMTAM ifif >50>50 yrs.yrs.

AC x 4AC x 4++ TAMTAM ifif >50>50 yrs.yrs. OperationOperation


NSABP B-27 Trial Eligibility: Operable Breast Cancer

• Diagnosis by fine-needle aspiration or core biopsy• Palpable on physical examination(T1c-3 N 0, M 0 / T 1-3, N 1, M 0)• Movable in relation to chest wall and skin• Nodes of any size but not fixed to each other or to adjacent structures• No arm edema



NSABP B-27 Trial (cont.) Treatment Regimen

Chemotherapy: doxorubicin, 60 mg/m2

cyclophosphamide, 600 mg/m2

Docetaxel: 100 mg/m2

Tamoxifen: 20 mg, orally, daily for five years(beginning on day 1 of chemotherapy)Radiation: Only for patients who had lumpectomy; done after surgery (arms I and II) and after treatment with docetaxel) (arm III)

Weekly (wkly) paclitaxel (P) followed by FAC as primary systemic chemotherapy (PSC) of operable breast cancer improves pathologic complete remission (pCR) rates when compared to every 3-week (Q 3 wk) P therapy (tx)

followed by FAC- final results of a prospective phase III randomized trial.Marjorie C Green, Aman U Buzdar, Terry Smith, Nuhad K Ibrahim, Vicente Valero, Marguerite Rosales, Massimo

Cristofanilli, Daniel J Booser, Lajos Pusztai, Edgardo Rivera, Richard Theriault, Cynthia Carter, Sonja E Singletary, Henry M Kuerer, Kelly Hunt, Eric Strom, Gabriel N Hortobagyi

Proc Am Soc Clin Oncol 21: 2002 (abstr 135)

Pathologic Complete Remission Rates (Breast and Lymph Nodes) : Weekly vs. Q 3 Week Paclitaxel

Node Positive Node Negative

Weekly (n = 50) Q 3 Week (n= 51) Weekly (n = 68) Q 3 Week (n = 67)

pCR 14 (28%) 7 (13.7%) 20 (29.4%) 9 (13.4%)

Weekly Paclitaxel is superior to q 3 weeks.




Endocrine Therapy

Drugs Targeting Estrogen and It’s Receptor Drugs Targeting Estrogen and It’s Receptor in Breast Cancerin Breast Cancer

EstrogenEstrogen

Cell Cell Growth Growth and and DivisionDivision

Estrogen Receptor

SERMS (tamoxifen, SERMS (tamoxifen, raloxifene), SERDS raloxifene), SERDS (fulvstrant)(fulvstrant)

Aromatase Aromatase inhibitors, ovarian inhibitors, ovarian suppressionsuppression

Aromatase InhibitorsAdrenal HormonesAdrenal Hormones

CortisolCortisol AndrostenedioneAndrostenedione AldosteroneAldosterone

EstradiolEstradiol

TestosteroneTestosteroneEstroneEstrone

Aromatase inhibitors Aromatase inhibitors block post-menopausal block post-menopausal estrogen productionestrogen production

Anastrozole (Arimidex)Anastrozole (Arimidex)Letrozole (Femara)Letrozole (Femara)Exemestane (Aromasin)Exemestane (Aromasin)




Letrozole Is More Effective Neoadjuvant Endocrine Therapy Than Tamoxifen for ErbB-1– and/or

ErbB-2–Positive, Estrogen Receptor–Positive Primary Breast Cancer: Evidence From a Phase III

Randomized TrialBy Matthew J. Ellis, Andrew Coop, Baljit Singh, Louis Mauriac, Antonio Llombert-Cussac, Fritz Ja¨nicke, William

R. Miller, Dean B. Evans, Margaret Dugan, Carolyn Brady, Erhard Quebe-Fehling, and Mieke BorgsJ Clin Oncol 19:3808-3816.

Conclusions Neoadjuvant therapy: Increases the likelihood of breast conservation

somewhat. Does not adversely affect survival excepting a

small risk of locoregional failure. More is likely better – i.e. add the taxane Endocrine receptor status will affect the outcome

and may need to be treated upfront, but chemo has more robust data.

Randomized comparison of endocrine vs chemo vs both is currently lacking for the ER/PR + pt.

Does a cCR need surgery? Is Surgery Necessary After Complete Clinical

Remission Following Neoadjuvant Chemotherapy for Early Breast Cancer?

By A. Ring, A. Webb, S. Ashley, W.H. Allum, S. Ebbs, G. Gui, N.P. Sacks, G. Walsh, and I.E. Smith

J Clin Oncol 21:4540-4545

MBC

Surgery

no role in cure

Only palliative

Chemotherapy

Hormone Therapy

Biological Therapy

EFS 20-30%

CR less than 5%

Radiation Therapy

Palliation Only

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Adjuvant treatment in early and localy advanced breast cancer