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N. El Saghir - Breast cancer - State of the art for early breast cancer
1. State of the art for
Early Breast Cancer
EASO Masterclass
October 27-29, 2011
Nagi S. El Saghir, MD, FACP
Professor & Director,
Breast Center of Excellence
NK Basile Cancer Institute
American University of
Beirut, Beirut, Lebanon
2. Breast cancer incidence and mortality
• Breast Cancer is most common in
women, except for skin
cancers, worldwide, including most Arab
countries
• Breast cancer is the second leading cause
of cancer death in women (1st: lung
cancer): Arab countries have no reliable
mortality statistics
• Death rates declining since 1990s as a
result of: - earlier
detection, screening, increased awareness, &
improved treatment.
3. Breast cancer in Arab countries
• National & Regional Registries: Increasing
• Frequency data: 14-42% of all women’s cancers
• ASR Incidence Rates: 9.5- 46 (up to 69/ 100.000)
• Young Age at presentation: Median: 48-52 yrs:
50% of cases < age 50
(USA & Europe: 25% are < 50; 50% are >age 63)
• High proportion of Locally advanced and
metastatic disease at presentation: 60-80%: (LABC
is decreasing because of increased awareness!)
• High rates of Mastectomy: 88-60% (…Decreasing)
• Low percentages of in-situ: <5% (… Increasing!)
Adapted from El Saghir et al, Intl J Surg. 2007 Aug;5(4):225-33
4. Heterogeneity of Breast Cancer
• Breast Cancer is not an only one disease:
Breast Cancer is a heterogeneous disease
• Different histologies and Receptors
• Different biological behaviors
• Different invasive potentials, different Stages:
Local / Regional / Metastatic
• Different Host characteristics
5. TNM staging of Breast Cancer
• Early Breast Cancer: I & II
• Locally Advanced Breast Cancer: III
• Metastatic Breast Cancer: IV
… & use of new receptor and molecular
classification
6. Molecular Subtyping of breast cancer
Heterogeneity of Breast Cancer is evident by different
receptors expression
- Estrogen Receptors (ER)
- Progesterone Receptors (PR)
- HER2/neu Receptors (HER2 aka ErbB2)
• New Molecular Classification incorporates
- Receptors
- Tumor Grade
- Prediction of biological behavior of disease
Gene expression profiles
validated by clinical follow-ups of patients
7. Molecular Classification of Breast Cancer:
Phenotype-expression and Gene-profiling
• ER positive, HER2 negative:
Luminal A Group
(mostly grade 1)
• ER positive, grade 3, or HER2-pos:
Luminal B Group
(mostly grade 3)
• ER negative, HER2-pos
HER2/neu-Overexpressive Group
(mostly grade 3)
• ER negative, PR negative, HER2-neg:
Triple Negative Breast Cancer
(Express breast epithelial cell markers
CK5/6 and HER1: Basal-like tumors:
Sorlie, et al. PNAS 2001
(mostly grade 3)
Sorlie et al. NEJM 2004
8. Gene microarrays, subtypes, and probability of
metastasis and of survival in early breast cancer
Time to Distant Metastasis
Of 4 subtypes of Breast cancer
Overall Survival
Of 4 subtypes of breast cancer
Luminal A & B: Patients do
BETTER
HER2/neu overexpressors &
TNBC: Patients do WORSE
Sorlie, et al. PNAS 2001
9. Breast Cancer managemnt:
Diagnosis Workup Treatment
Abnormality discovered by Screening, or Accidental or
Symptomatic:
1- Clinical Examination: Breast & Axilla, systemic exam
2- Mammography (+/- Breast Ultrasound)
3- Diagnosis by Fine Needle Aspiration or Core Biopsy
(Frozen Section followed by Mastectomy one-time
procedure is not acceptable!)
4- Metastatic work-up: Staging
5- Discuss treatment options: Amongst physicians, and
with patient (& family)
10. Assessment of patient with breast mass
• After imaging: Proceed with a
Biopsy:
FNA or Core Biopsy
There is rarely ever need to take the patient
immediately for surgery the same day or
next day!
Excisional biopsy or frozen section may be
needed only at rare times, when diagnosis
could not be made by biopsy!
11. •
Spiculated irregular mass, highly suspect mass :
Diagnosis is to be made before any treatment is applied
12. Diagnosis: When to do an FNA?
• If you plan Primary Surgery, then FNA might be
enough to reach a diagnosis
• If the Tumor is clinically & radiologically suspect
• FNA is easier, less discomfort to patient and
cheaper
• FNA is not for used for microcalcifications
because it does not differentiate DCIS from
Cancer
• FNA cytology needs training and expertise
13. When to do a Core Biopsy?
1. If you plan Neo-adjuvant therapy
2. If you need to know receptors before
any treatment
3. Cases of microcalcifications only
4. Nonpalpable lesions
5. Less suspicious lesions
6. Non-diagnostic FNA, …
14. FNA or Core Biopsy
• Histological development:
Normal duct In-Situ Cancer Cancer (Invasive)
15. Clinical Case: FNA or Biopsy ?
M.O.: 40 y-o-w-f
Large mass; nipple
retraction and oozing for
several months
• Nipple retraction and oozing, mass
Locally Advanced Br Ca
This patient needs pre-op
therapy:
a core biopsy for
Pathology & Receptors
16. Heterogeneity, hormone
receptors, and definitions of
positivity
New guidelines for Receptor positivity: >1% of cells
17. HER2-positive breast cancer
• Up to 25% of women with Early Breast Cancer have
HER2-positive disease
• Aggressive form of the disease: Early progression and
poor prognosis
(recurrence within 2-3 years)
• HER 2 positivity is an independent risk factor
• HER2-positive means: HER2 +++, or HER++ with FISH+
Slamon et al 1987, 1989, 2001;
Goldhirsch et al 2005; Marty et al 2005
18. HER2 receptors’ expression: IHC and FISH
testing: Definitions and guidelines
3+: Positive 2+ Equal: Equivocal
Needs FISH Test
1+: Negative 0: Negative
19. Testing for ErbB2/HER2:
Quality, Volume, Experience & Relability!
Cell surface
Protein expression
++ is Equivocal
then do FISH testing Gene amplification: FISH +)
(if no amplification: FISH -)
What is +++: >.30% of cells complete membrane staining
Remember: Clinical trials used >10% criteria
What is exactly ++ ? How does your pathologist choses cells for FISH testing?!
20. Surgery for Early Breast Cancer
1. Breast Conserving Therapy (Surgery +
RT): Partial
Mastectomy, Lumpectomy, Quadrantecto
my
2. Mastectomy
3. Mastectomy + Reconstruction
4. Sentinel Lymph Node Biopsy (SLNB)
5. Axillary Lymph Node Dissection (ALND)
Veronesi U; Fisher B, Giuliano A, Krag D; and others,
21. BCT vr MRM +/-RT BCT vs MRM in TNBC
Abdulkarim, et al. J Clin Oncol 2011;29:2852-2858
22. B-32 OS
NSABP Protocol B-32
100
80 Overall Survival for Sentinel Node Negative Patients
% Surviving
40 60
Trt N Deaths
20
SNR+AD 1975 140
SNR 2011 169 HR=1.20 p=0.117
0
Data as of December 31, 2009
0 2 4 6 8
Years After Entry
* 300 deaths triggered the definitive analysis
* 309 reported as of 12/31/2009 Krag et al, ASCO 2010
23. ACOSOG Z 0011
in patients with positive SLNB
DFS and OS: Completion ALND or not
Disease Free Survival Overall Survival
100 100
90 90
80 80
70 70
% Recurrence-Free and Alive
60 60
% Alive
50 50
40 40
30 30
ALND 20 ALND
20
No ALND No ALND
P-value = 0.14 P-value = 0.25
10 10
0 0
0 1 2 3 4 5 6 7 8 0 1 2 3 4 5 6 7 8
Time (Years) Time (Years)
Giuliano AE et al, ASCO 2010, JAMA 2011
23
25. Breast and Axilla Conservation!
• Breast Conserving Therapy (+ RT) is at least as
good as Total Mastectomy
• New data is emerging that BCT (+RT) may be even
superior to Mastectomy in TNBC!
• Sentinel Lymph Node Biopsy has become standard
of care for EBC with clinically negative axilla
• SLNB negative: Stop there
• SLNB positive: Select cases for completion ALND
• Every surgeon and every hospital that treats breast
cancer should be equipped and gain expertise in
SLNB for Early Breast Cancer
26. Radiation Therapy (RT) in EBC
• BCT = Partial breast surgery + RT
• Post-mastectomy Irradiation:
• BCT: partial breast surgery + RT
• Post-Mastectomy RT:
T >5cm; N2 and above: Always
N1: More & more patients are being offered
the option of post-mastectomy RT.
Reminder: For every 1 local recurrence prevented at 5
years, there is one life saved at 15 year! EBCTG
overview
27. Adjuvant Post-operative Systemic
Therapy for Early Breast Cancer
• Eliminates micrometastases
• Reduces recurrences
• Improves survival
• It is traditionally based on TNM stage, and
known prognostic and predictive factors
28. Factors used to choose type of
adjuvant therapy
• Patient-related factors: Age, Menopausal status,
known risk factors, hereditary factors, comorbidities
• Tumor-related factors:
- Disease history
- Anatomical stage: TNM
- Biological characteristics: Grade, Differentiation,
LVI, Receptors,
• Predictive factors of response to certain therapies
• Known toxicities of therapy
29. Benefit from adjuvant chemo, CMF or A
ADJUVANT Therapy & BREAST CANCER MORTALITY (Peto R, SABCS 2007)
•CMF chemo vs no chemo Anthracycline-based chemo vs CMF chemo
30. Common regimens for adj. chemo in EBC
• Non-anthracyline regimens:
CMF: Cyclophosphamide, Methotrexate, 5-FU
- Classical CMF q4w: Oral C 100/m2x14d, M 40/m2 F 600/m2 days 1 & 8)
- IV CMF q3w: C (600/m2) M (40/m2; 30/m2 if >60) F (500/m2)
• CAF not > CMF in INT0102 trial (Hutchins JCO 2006)
• CMF = EC (Belgian Trial, follow-up 15 years E 100 > E60)
• Metaanalysis of 4 phase III trials and Oxford overviews:
Anthracycline-regimens > CMF
• CMF remains most useful in luminal cancers, low bulk
tumors, patients who refuse hair loss, less toxic
regimen, older patients.
31. Common Adj. chemo regimens in EBC
• Anthracycline regimens, without taxanes:
AC: A (60mg/m2), C (600mg/m2): Q3w x 4 cycles for
node-negative patients
CAF or FAC: F (500mg/m2), A (50/m2), F (500mg/m2) x 6 cycles
used for node-positive patients
Epirubicin may be used instead of Adriamycin
(Example: E (90/m2) C (600/m2) instead of AC (60,600/m2)
• Higher dose Epirubicin: C E (100) F > CAF
• A (75m/m2) q3w x 4 followed by CMF x8 (Bonnadona, et al)
32. Common Adj. chemo regimens in EBC
• Anthracycline regimens, with taxanes:
Sequential administration (preferred):
• AC-T: AC-Paclitaxel or AC-Docetaxel:
A (60mg/m2), C (600mg/m2): Q3w x 4 cycles followed
by Paclitaxel or Docetaxel:
• AC-Paclitaxel: 175/m2 IVD over 3 hours q3w x 4 cycles:
(Example CALGB 9344 study)
Curently, preferred use of Paclitaxel is weekly dosing:
Paclitaxel 80mg/m2 qweek x 12 weeks
(P q1w = D q3w & > to q P 3w or D qw :Sparano 2008).
• AC-Docetaxel: (D100mg/m2 q3w x 4 cycles)
• FECx3 – D x3 (PASC01 study)
• Sequencing: Superior efficacy and less cardiotoxicity
33. Common Adj. chemo regimens in EBC
• Anthracycline regimens, with taxanes:
Concurrent: TAC (T 75/m2, A 50/m2, C 600/m2), plus g-csf
BCIRG 001, updated:
TAC > FAC
Useful in certain younger patients
more aggressive disease
More toxic regimen, requires g-csf
34. Common Adj. chemo regimens in EBC
• Anthracycline regimens, with taxanes:
Sequential Dose Dense Regimens:
AC-T: q 2 weeks , with g-csf support (Citron, et al. CALGB
study 9741: JCO): Benefit mostly for ER-, HER2+ pts
T-CEF (MD Anderson Cancer Center)
Paclitaxel (80mg/m2) qw x 12 weeks followed by
CEF (500/m2, 75/m2, 500mg/m2) q 3w x 4 cycles
35. Common Adj. chemo regimens in EBC
• Taxanes, without anthracyclines:
• TC > AC: (Jones S, et al JCO 2010) useful in more
aggressive cases, useful when contra-indication for
anthracyclines)
• T-CMF
• TCH (Docetaxel + Carboplatin + Trastuzumab) in HER2 positive patients:
see following slides)
36. Adjuvant targeted therapy
trastuzumab in HER2 positive EBC
Major Trials in the Adjuvant Setting: (Presentations in
2005 and updates in 2011):
• HERA (positive, 1 year trastuzumab)
• NSABP-B31 (Positive, 1 year trastuzumab)
• NCCTG N9831 (Positive, 1 year trastuzumab)
• BCIRG 006 (Positive, has arm without anthracyclines)
• FinHer (Smaller trial, short duration Trastuzumab)
• PACS-04 (Smaller trial, negative)
37. Adjuvant Therapy for patients
with ERB2-positive breast cancer
• Anti-HER2 Benefit is established for patients with
HER2 +++ or HER2 ++ with FISH positive
• Patients are given Adjuvant Chemotherapy +
Trastuzumab +/- Hormonal therapy
Recurrence: is cut by 50%;
Risk of Death: is cut by 30%
Slamon et al 1987, 1989, 2001;
Goldhirsch et al 2005; Marty et al 2005
38. Design & 2005 Results of 4 major positive
Adjuvant Trastuzumab in EBC
•HERA •BCIRG 006
•Observation
•IHC / FISH •FISH
•1 year
(n=5090) (n=3222)
•1 year
•2 years
•1 year
•NCCTG N9831
•NSABP B-31
•IHC / FISH •IHC / FISH
•1 year
(n=3505) (n=2030)
•1 year
•1 year
•Doxorubicin + •Docetaxel +
•Standard CTx cyclophosphamide •Docetaxel carboplatin •Herceptin® •Paclitaxel
Piccart-Gebhart et al 2005; Romond et al 2005; Slamon et al 2006
39. Summary of Benefit of adjuvant
Trastuzumab therapy in EBC
• Trastuzumab improves DFS
benefits across 5 out of 6 major trials
• Trastuzumab reduces the risk of death by one-
third in 4 trials
• Trastuzumab provides DFS benefit, irrespective
of LN status (T1 N0 M0 Patients)
Joensuu et al 2006;
Slamon et al 2006; Perez et al 2007;
Smith et al 2007; Spielmann et al 2007
40. HERA study Update: New 4-years F-Up
Results on Treatment & Observation Arms
•HER2-positive early breast cancer
(IHC 3+ and / or FISH+)
n=5102
•Surgery + (neo)adjuvant chemotherapy
+ radiotherapy
•Herceptin •Herceptin
•Observation
•q3w x 1 year •q3w x 2 years
•Option to cross
over to Herceptin
• 50% pts crossed to treatment arm
•(after IA, 2005)
•IHC, immunohistochemistry; FISH, fluorescence in situ hybridisation Piccart; Smith; Gianni
41. DFS benefits of 1-year adjuvant
trastuzumab persist at 4-year
100 follow-up (ITT)
1-year trastuzumab
Alive and disease free (%)
80
Observation 6.4%
60
40
4-year
Events DFS HR 95% CI P-value
20
458 72.2 0.76 0.66–0.87 <0.0001
369 78.6
0
0 6 12 18 24 30 36 42 48
Months from randomisation
No. 1698 1564 1440 1363 1297 1240 1180 992 712
at risk 1703 1619 1552 1485 1414 1352 1280 1020 854
CI, confidence interval; HR, hazard ratio; ITT, intent to treat Gianni, et al. 2011
42. HERA 4-year Follow-up: Summary
• 1 year of adjuvant trastuzumab following
chemotherapy provides significant and long-
lasting DFS benefits
(Crossover confounded the OS analysis in the ITT population)
• Patients crossed over from observation arm to
Trastuzumab had fewer DFS events (HR 0.68)
• The overall incidence of cardiac dysfunction
remained low with longer follow-up
Gianni, et al. Lancet Oncology. Epub 25 Feb, 2011
43. St Gallen guidelines for HER2-positive
Early Br Ca (Since 2007)
•Herceptin® •Chemoth •Hormonal therapy
•Endocrine
responsive
•HER2-positive
•Endocrine
non-responsive
• HER2 positivity alone confers either intermediate- or high-risk status
– 1-year adjuvant trastuzumab is current standard
– Role of 2-year adjuvant Trastuzumab is unknown
– Shorter durations: 6 months vs 12 months: Ongoing French & Italian Trials
• Patients should also receive
– Chemotherapy (prior, or concurrent); Hormonal therapy, as indicated
•Adapted and modified from Goldhirsch et al 2007
44. Adjuvant Trastuzumab for T < 1cm ?!
There is some evidence that HER2 positivity
carries an adverse prognostic significance even in
patients with tumors <1 cm
• MD Anderson retrospective review: HER2-
positive small tumors: worse prognosis
Chia S, et al. J Clin Oncol 2008; 26: 5697–5704, Curigliano G, et al. J Clin
Oncol 2009, Smith IE. Breast 2009; 18 (Suppl 1): S17 (Abstr S41).
45. What about smaller tumors & negative LN?
(DFS benefit for (For T1 N0 M0 Patients ; T >1cm)
•HERA •N-
•1-3+ nodes
•>4+ nodes
•Not assessed
•N9831 / B31 •N-
•1-3+ nodes
•4-9+ nodes
•>10+ nodes
•BCIRG 006 •N-
•ACDH
•N+
•N-
•DCarboH
•N+
•0 •0.5 •1.0 •1.5 •2.0 •2.5
•Favours Herceptin® •Favours no Herceptin®
•Hazard ratio
•Size of square represents sample size; horizontal bars indicate 95% confidence intervals
•Perez et al 2007;
•N, node Slamon et al 2006; Smith et al 2007
46. St Gallen 2011 Experts’ votes on
Adjuvant Therapy for HER2-positive
Early BC (including small tumors)
Trastuzumab (+chemo) for 1yr Yes No Do not know
Chemotherapy Duration x 1yr 100% - -
Trastuzumab for T1b (5-10mm) 79% 15% 6%
Trastuzumab for T1a 24% 61% 15%
Trastuzumab +/- adj. endocrine if 67% 23% 9%
chemo is contraindicated
Trastuzumab for < 1 year 26% 63% 11%
according to resources (low)
(OK : Better than nothing)
Personal notes and
Goldhirsch et al. Ann Oncol. 2011 Aug;22(8):1736-47
48. Hormonal Therapy for Breast Cancer
• Blockade of Estrogen Receptors
– Selective Estrogen Receptor Modulators:
- Tamoxifen 20 mg / day: Useful for treatment and chemoprevention
- Toremifene: cross-resistant with tamoxifen; little usage
- Raloxifene: used for osteoporosis and chemoprevention
– Pure Antiestrogen Receptor /Estrogen Receptor Down-regulator:
- Fulvestrant
• Suppression of Estrogen Synthesis
– Ovarian Ablation
- Surgical (Laparoscopic) Oophorectomy
- Irradiation of ovaries
- Chemo-induced amenorrhea
--- Ovarian Suppresion : LHRHa (GnRHa)
– Aromatase Inhibitors (in Post-menopausal women): Anastrozole,
Letrozole, Exemestane
49. Landmark study: NSABP B-14
Adjuvant 5-yr Tamoxifen vs Placebo
Tumors ER > 10 fmol/mg
Node Negative
Stratification:
age,T size,
quantitative ER,
type of surgery
5 YEARS
PLACEBO TAMOXIFEN
50. NSABP B-14
Effects of TAM on Disease-Free Survival
100 T
90 T
T
T
% 80 T
P = <0.000005
70
PLACEBO
60
T TAM
0 1 2 3 4 5
YEAR
NSABP
51. Early Breast Cancer Trialists Cooperative Group
Peto, et al. Lancet 1998; 351: 1451-67
Five Years of Tamoxifen
52. Benefits (reduced Recurrence) from Tam Therapy:
~5 years Tam vs no Tam (Peto R, SABCS 2007)
•ER-poor disease •ER+ disease
•ER+ disease
53. Benefits (reduced Mortality) from hormonal tx:
~5 years tamoxifen vs no Tamoxifen (Peto R, SABCS 2007)
•~5 years tamoxifen vs. Not, ER+ only
BREAST CANCER MORTALITY
55. If you are still hesitant, you may follow ABCSG-12
Tam + LHRHa + Zoledronic Acid
(Gnant et al ASCO 2008)
Primary Endpoint: Disease-Free Survival
100
90
80
Disease-free survival, %
70
60
50
40
30 No. of Hazard ratio (95% CI)
events vs No ZOL P value
20 ZOL 54 0.643 (0.46 to 0.91) .011
10 No ZOL 83
0
0 12 24 36 48 60 72 84
Time since randomization, months
Number at risk
No ZOL 904 838 735 565 441 265 161 60
55 ZOL 899 851 744 573 434 270 131 59
56. Choices of Adjuvant hormonal therapy
in premenopausal women with EBC
• Tamoxifen: 5 years is standard
(ATLAS study 5 vs 10 years: ongoing, earlier report
is promising positive: Peto et al, SABCS 2009)
• Tamoxifen + LHRHa + Zoledronic Acid: supported by
ABCSG-12 trial
• Tamoxifen + switch to AI when patient becomes
menopaused (after 2-3 years or more)
• Importance of Chemo-induced amenorrhea
• Tamoxifen + LHRHa: Role of Ovarian
Ablation/Ovarian Suppression: No final word yet!
57. Adjuvant hormonal therapy
in post-menopausal women
• How to improve on adjuvant tamoxifen?!
Add or replace by AI:
• This was the start of a very long chapter in
hormonal therapy of breast cancer:
• AI are more effective in Metastatic Breast Cancer:
AI were moved into the Adjuvant (and Neo=Adjuvant)
settings
ATAC, MA-17, 1-98, IES, …, …
58. ADJUVANT TRIALS of Tamoxifen & AI
Tamoxifen x 5y Upfront, head to head comparaison
ATAC (A vs T), BIG 1-98 (T vs
A.I. x 5y
L), TEAM (T vs E)
Tamoxifen x 5y Sequential: IES (Exem) ,1-98 (T vs L)
Tamoxifen A.I. ARNO (A vs T), ABCSG-8 AvsT, ITA (A vs T)
Placebo x 5y MA-17: Extended
Tamoxifen x 5y
A.I. x 5y L vs Placebo
Tamoxifen x 5y “Reverse” Sequential
A.I. Tamoxifen Big 1-98 arm
60. MA.17 Post-Unblinding: (DFS at 4yr: 93% vs 87%)
Median F/U
30 Months 54 (16 –86) Months
Letrozole n= 2593 Letrozole (LET) n = 2457
Tamoxifen
n = 5187
Placebo n= 2594 No Letrozole (PLAC) n = 613
5 years
5 years
Letrozole (PLAC-LET) n = 1655
1998 2003 2005
Unblinding Benefit for switching
Ingle et al Goss et al: & for late switching!
Goss PE, et al. SABCS. 2005. Abstract #16.
61. Intergroup Exemestane Study T then T vs Exem.
Disease-Free Survival
Patients Surviving Free of Disease (%)
100 Exemestane
75
Tamoxifen
50
HR 0.68
25
p<0.001
0
0 1 2 3 4
Years after Randomization
No. of Events/No. at Risk
Exemestane 0 / 2362 52 / 2168 60 / 1696 44 / 757 20 / 201
Tamoxifen 0 / 2380 78 / 2173 90 / 1682 76 / 730 18 / 185
62.
63. UPFRONT AI TRIALS:
Summaries & Combined Analysis
Ratio, annual
event rates
Upfront AI studies: (Al:Tam) 2P
Any recurrence 0.77 (SE 0.05) <0.00001
ATAC Isolated local* 0.70 (SE 0.10) 0.003
& Isolated
0.59 (SE 0.12) 0.0009
BIG 1-98 contralateral*
Distant* 0.84 (SE 0.06) 0.009
Any distant 0.82 (SE 0.06) 0.002
* As first event, heterogeneity, p = 0.08
Dowsett M et al JCO 2009
No significant reduction of mortality, yet!
64. SWITCHING TRIALS:
Combined Analysis and summaries
Ratio, annual
event rates
(Al:Tam) 2P
Switching Trials: Any recurrence 0.71 (SE 0.06) <0.00001
IES Isolated local* 0.60 (SE 0.13) 0.002
ABCSG 8 Isolated
0.65 (SE 0.17) 0.03
ARNO contralateral*
Distant* 0.76 (SE 0.07) 0.001
ITA
Any distant 0.77 (SE 0.06) 0.0009
* As first event, heterogeneity, p = 0.4
Dowsett M et al JCO 2009
Switching favored!
67. SABCS 2009
Updates on switching adjuvant endocrine
therapy trials
Median
Trial Nr. Pts Design F.up Results
Tam 7.5 y • E remains superior
IES 4724 Tam 2-3y R DFS HR 0.82 (0.73-
Exem 0.92)
OS HR 0.86 (0.75-0.99)
• E seems to ↓ bone mets
• E seems to ↓ non breast
2d cancers
NCIC-CTG 5168 Tam 5y Letrozole • Larger absolute benefit
R
MA17 (n = 889 Placebo in pre compared to
postmen. (≈ 10%) in
premen.) delayed let
both N+ and N- disease
observ.
Bliss, Goss, SABCS 2009
68. Conclusions and take home messages
for adjuvant AI and Tamoxifen
Premenopausal women, derive a large benefit from
the switching strategy, whether LN+ or LN-: Patient
who is started on Tam as premenopaused, switch to
AI when becomes “definitely” meno-paused
Patients at higher risk of recurrence (more positive
nodes, etc) benefit more from upfront AI
Node-negative patients: In general, switch strategy is
fine
If patients have poor tolerance to AI, reverse
switching to Tamoxifen seems fine
69. Adjuvant Chemo based on Anatomy only!
• Larger T size & Higher N stage: Yes for using
chemotherapy (& targeted therapy if HER2-positive)
• What to do in patients with Smaller
Tumors?!
May not need chemotherapy!
May get help from Genomics & Microarray studies:
- RS-21: Recurrence Score 21 (Oncotype DX)
- Amsterdam 70-gene signature (Mammaprint)
70. Role of Genomics in adjuvant therapy
• Retrospective Validation:
of multigene assays (Amsterdam 70-gene, RS-21)
using paraffin blocks of tumors:
NSABP: B-14 (Tam vs placebo)
NSABP: B-20 (Tam vs Chemo + Tam)
SWOG 8814 (Tam vs CAF + Tam)
• Prospective Randomized definitive trials:
- MINDACT (Study BIG / EORTC):
Validation of the 70-gene Amsterdam signature score
- TAILORx (Study in the USA):
Validation of the 21-gene Recurrence Score
71. Established Rates of Distant Recurrence:
vs Ranges of RS-21 score
Paik, et al. NEJM 2004, 351;27
75. Adjuvant therapy for small tumors:
• Anatomo-pathology remains important
• Biology is gaining more and more importance
Hormone receptor negative require chemotherapy
Trastuzumab is indicated in most patients with HER2
positive tumors, but probably not all of them!
Not everybody benefits from addition of chemotherapy
Many patients can be treated with hormonal therapy
alone, especially well differentiated, grade 1, with strongly
positive hormone receptors:
TNM, histology, IHC, receptors, biology, genomics: Helps us
to better tailor adjuvant therapy!
76. State of the art in
Early Breast Cancer
• Most areas covered!
• Thank you for your attention
-----------------------------------------------------
Back-up slides: 2 Cases
• Locally Advanced Breast Cancer
• and relatively large Early Breast Cancer
with positive Lymph Nodes) Breast
Cancer
• (HER2+ and HER2-)
77. HER2-negative Locally Advanced Br Ca
(& relatively Large Early Breast Cancer)
• NM: 52 y-o-f, diagnosed in 2008
• cT2 (3.2x2.6cm) cN1 (FNA+) M0;
• IDC; ER++, PR+, HER-
• Neo-Adjuvant chemo: AC – D (NSABP B-27 protocol)
cCR
• Partial Mastectomy + ALND
yT0 yN0 Mo
• Radiation Therapy
• Tamoxifen, with plans to switch to AI once definitely
menopaused
• 2011: No Evidence of Disease; already switched to AI
78. HER2-positive LABC
(& relatively large Early Breast Cancer)
• NH: 56 y-o-f, diagnosed in 2009
• cT3 (7x8cm) cN1 M0; IDC;
ER-, PR+, HER+++
• Neo-Adjuvant chemo: T(H)- CEF(H) [MDACC regimen]
Paclitaxel 80/m2 qw x 12 - CEF x4
cCR
• MRM + ALND
yT0 N1 (1/33, treatment effects, DCIS) Mo
• Radiation Therapy
• Letrozole
• Trastuzumab x1 yr
• 2011: Remains with No Evidence of Disease
79. Multi-Disciplinary Management of cancer
338 Physicians surveyed: 72% hold TUMOR BOARDS
52% only: Hold it weekly
57% attend Tumor Boards at Neighboring Hospitals
60% attend it for group opinion and discussion
93% agree it should become mandatory
100% agree to have at least a MINI-TUMOR BOARD
with whoever is available (Ex: Surg +Radiol +/- Oncol +/- Path
Notas del editor
ReferenceGianni L, et al. Treatment with trastuzumab for 1 year after adjuvant chemotherapy in patients with HER2-positive early breast cancer: a 4-year follow-up of a randomized controlled trial. Lancet Oncology Epub 25 Feb, 2011. DOI: 10.1016/S1470-2045(11)70033-X.