adjuvant treatment in early and localy advanced breast cancer
TRANSCRIPT
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
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
Multidisciplinary Cancer Breast Management
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
Multidisciplinary Cancer Breast Management
Neoadjuvant Chemotherapy (cont.)
•Goals:– Decrease tumor size– Minimize surgery– Establish tumor sensitivity
•Appropriate treatments:– Chemotherapy– Tamoxifen or aromatase inhibitors– Radiation therapy
Multidisciplinary Cancer Breast Management
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
Multidisciplinary Cancer Breast Management
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
Multidisciplinary Cancer Breast Management
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
Multidisciplinary Cancer Breast Management
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
Multidisciplinary Cancer Breast Management
Multidisciplinary Cancer Breast Management
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.
Multidisciplinary Cancer Breast Management
Multidisciplinary Cancer Breast Management
Multidisciplinary Cancer Breast Management
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)
Multidisciplinary Cancer Breast Management
Multidisciplinary Cancer Breast Management
Multidisciplinary Cancer Breast Management
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
THANKS