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EARLY STAGE BREAST CANCER Operable local-regional inv cancer (Stage I, II, some IIIA). Elshami M. Elamin, MD Medical Oncologist Central care Cancer Center www.cccancer.com Wichita, KS - USA. TNM Staging. Stage IA:T1 ( < 2 cm) Stage IB:T0-1, N1mi Stage IIA:T0-1, N1 or - PowerPoint PPT Presentation
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Elshami M. Elamin, MDMedical Oncologist
Central care Cancer Center
www.cccancer.com
Wichita, KS - USA
EARLY STAGE BREAST CANCER
Operable local-regional inv cancer(Stage I, II, some IIIA)
1
TNM Staging
Stage IA: T1 (< 2 cm) Stage IB: T0-1, N1mi Stage IIA: T0-1, N1 or
T2 (>2 - 5cm) Stage IIB: T2 + N1
T3 (>5cm) Stage IIIA: T0-2 + N2
T3 +N1-2 (N2 = adv IIIA)
2
Work-up H/P CBC, LFT, Alk Mammo +/- US Path review Bone scan detects mets
Stage I = 5.1% Stage II = 5.6% T3N1 = 14%
Liver US, C-x-ray detect mets: Stage I,II = None
CT abd+/-pelvis, Chest imaging, Bone scan; Should be considered for T3N1
Staging PET not recommended 04/22/23 3
PROGNOSTIC FACTORS
4
Lymph Nodes
Node +ve: 50-70% Risk of relapse
10 LN+ve: 80% Risk of relapse/mets Node –ve:
Up to 20-30% Risk of relapse
Negativity is reliable only if 6-10 LN were removed and examined
5
Axillary LN
5 Yr Survival (%)
N - 1-3 + 4 +
Moon et al 89 68 48
Carter et al 92 81 57
Valagussa et al 88 69 42
Ariel et al 81 66 48
Fisher et al 78 62 326
Tumor size
5 Yr Survival (%)
<2cm 2-5cm >5cm
Carter et al (24,740 pts) 91 80 63
Schottenfeld (304 pts) 92 71 55
Nemoto et al (13,384 pts) 62 49 34
7
Estrogen Receptor
DFS (%)* OS (%)#ER+ ER- ER+ ER-
NSABP74 66 92 82San Antonio 76 67 84 75
* P value <0.001
# P value <0.0001
8
STEROID RECEPTORS
The best use of ER/PR is not in determination of prognosis but in the
selection of optimal adjuvant systemic therapy
9
Age
Young age is a significant predictor of local recurrence after breast conserving therapy
04/22/23 10
Histology Invasive ductal and lobular have similar
prognosis Pure tubular, mucinous or colloid, and papillary:
usually small, N-ve favorable prognosis (ER+, Her2 –ve) treat with breast conservation May omit systemic adj therapy (if T <3cm)
Pure or typical medullary has better prognosis than ductal but favorable as tubular or colloid. However, because pure/typical medullary is uncommon
and difficult to diagnose pathologically it is recommended to treat medullary same as inv ductal carcinoma.
11
Pathologic Factors
Histologic subtypes Histologic grade Nuclear grade Mitotic indix Vascular/lymphatic invasion Inflammatory response Tumor necrosis Mononuclear cell infiltration
12
Biologic Factors
S-phase Ki 67 Her-2/neu Tumor supressor genes P53
13
Principle of Her-2 neu testing IHC assay (Lab meets quality assurance standards for IHC methodology)
IHC 0, 1+ (negative) IHC 2+ (borderline)
FISH IHC 3+ (positive)
FISH assay (Lab meets quality assurance standards for Her-2 neu methodology
FISH non-amplified (negative) FISH borderline
IHC or Retest or Count additional cells
FISH amplified (positive)
HERmark (quantitative test) Her-2 Dual ISH assay detect both Her2 and chromos. 17
14
Molecular Subtypes of Breast Cancer
1. Luminal A: ER+ and or PR+ Her2 -ve2. Luminal B: ER+ and or PR + Her2+3. Her2: Her2+ ER-ve PR-ve4. Basal-like: ER-ve PR-ve Her2-ve,
cytokeratin 5/6+, and or Her1+5. Normal-like: negative for all
markers
BREAST CA SUBTYPES
Hormone responsive; ER/PR positive Luminal A and B disease by microarray
Her-2 neu overexpression; Herceptin responsive Her-2 neu overexpression by microarray
Non hormone responsive, non-Her-2 neu overexpressive;
poor prognosis TRIPLE NEGATIVE basal-like by microarray
16
Risk Categories
Low Intermed High(All) (> 1)
LN -ve -ve +ve Tumor size < 1cm > 1-2cm > 2cm ER/PR +ve +ve -ve Grade 1 1-2 2-3 Age > 35 <35
17
St Gallen's risk categories for Node
negative Low risk: ER/PR+ve and all of following:
pT < 2cm (inv component) G1 > 35Y
High risk: ER/PR -ve or ER/PR +ve + one of following:
pT> 2cm (inv component) G 2-3 <35Y
18
Surgical Options
Breast conservation Lumpectomy + ALN staging
MRM + reconstruction
21
Breast Conservation
CONTRAINDICATIONS
Absolute Multicentricity Diffuse microcalcifications Early pregnancy Previous RT Positive margins
Relative Tumor size vs breast size Tumor location, or >5 cm Collagen vascular disease
(excluding RA) Focally positive margin
22
Re-excision of Primary
Indications: Extensive Intraductal Component (EIC)
especially with close margins (<2cm) Positive/uncertain margins Residual microcalcifications
23
Margin status
Breast conserving surgery is predicted on achieving a negative margin
What if margins remain positive?! Mastectomy In selected cases may accept
microscopically focally positive margin, but with conditions:
Absence of extensive intraductal component Use of higher R.T. boost to tumor bed
24
ROLE OF LN DISSECTION
Diagnostic and/or Therapeutic? LN –ve:
70-90% 5YS 10% chance of death in 10Y
LN+ve: 50-70% risk of relapse 35% chance of death in 10Y
1-3 LN+ve: 60-80% 5YS >4 LN+ve: 30-50% 5YS
25
Sentinel L. Node Dissection
Candidates: Clinically -ve nodes Solitary T1 or T2 ?? High grade/extensive DCIS No large hematoma or seroma No neoadjuvant chemo
SLN can’t be identified or +ve: Formal axillary dissection
26
Breast conservation(Lumpectomy + RT)
MRM: S% Lump/RT: S%
NSABP 60 62
EORTC 73 71
Danish 82 79
NCI 75 77
28
Lumpectompy + RT
Local recurrence
Pts L% L+RT%
NSABP 1262 35 10
Milan 567 12 2
Ontario 837 35 11
Sweden 381 18 2
Scottish 585 25 6
British 418 35 1329
Post-MRM R.T. > 4 positive LN:
RT to chest wall + ICV LN + SCV LN +/- IM LN:
1-3 positive LN: Strongly consider RT to chest wall + ICV LN + SCV LN +/-
IM LN:
T > 5 cm or positive margins: Consider RT to chest wall +/- ICV LN/SCV LN/IM LN
T < 5 cm and margin <1mm: RT to chest wall
T < 5 cm, N negative, margins > 1mm: No RT
30
Is R.T. required for elderly?
Age > 70, Stage I, ER +ve treated with lumpectomy +/- RT Tam: Median f/u of 8.2Y
Local-regional recurrence rate: 1% vs 4%
No diff in OS, DFS or need for mastectomy
04/22/23 31
Why Neoadjuvant Therapy? Downstages the primary tumor in most women.
Allows a higher rate of breast preservation.
Provides an in vivo assessment of tumor response to the particular drug regimen and, hence, an opportunity to optimize therapy.
Pathologic complete response (pCR) after preoperative therapy is a powerful surrogate of long-term disease free survival.
It is hypothesized that a regimen that produces higher rates of pCR in the neoadjuvant treatment setting will also result in higher rates of long-term cure.
Why pre-Chemo SLND?
Pathologic LN CR following preop chemo
Guide local and systemic treatment
04/22/23 34
NSABP B-18
Preop AC: Breast conservation is more likely Improves DFS/OS in pt with Pathologic CR
No disease specific survival advantage over adj chemo in stage II
04/22/23 35
NSABP B-27
Three arms:1. Preop AC local therapy2. Preop AC/Doce local therapy3. Preop AC local therapy Doce
04/22/23 36
NSABP B-27
ACx4 surg 40% clinical CR 14% partial CR
ACx4 Taxotere100 x4 surg 65% cCR 26% pCR
AC-->surg-->Taxotere No improvement in lumpectomy Higher rate of pathologic CR with AC/Doce No DFS and OS diff
DFS favors preop Doce vs postop Doce in subset of pts with partial response to AC
37
MD Anderson regimen(Her2-neu +ve)
NeoAdj: Taxol X4 + Trastuzumzb CEF x4 + Trastuzumab (Total of 24 wks)
Trastuzumab increases path CR from 26 to 65.2%
04/22/23 38
Significantly Higher Pathologic Complete Remission Rate After Neoadjuvant Therapy With Trastuzumab, Paclitaxel, and Epirubicin Chemotherapy: Results of a Randomized Trial in Human Epidermal Growth Factor Receptor 2–Positive Operable Breast Cancer
Aman U. Buzdar, Nuhad K. Ibrahim, Deborah Francis, Daniel J. Booser, Eva S. Thomas,Richard L. Theriault, Lajos Pusztai, Marjorie C. Green, Banu K. Arun, Sharon H. Giordano,Massimo Cristofanilli, Debra K. Frye, Terry L. Smith, Kelly K. Hunt, Sonja E. Singletary,Aysegul A. Sahin, Michael S. Ewer, Thomas A. Buchholz, Donald Berry, and Gabriel N. Hortobagyi
MD Anderson protocol: prospective randomized phase III study were the goal of the study
was to demonstrate that the addition of trastuzumab to a complete 6-month preoperative chemotherapy regimen will increase pCR rate two-fold compared with chemotherapy alone.
The study was powered to detect a 20% improvement in the pCR rate (ie, from 21% to 41%)
Ongoing Anti-Her2 Neoajuvant NeoALTTO – BIG 01-06 (phase III):
Adj Lap/Traz/Taxol vs LT vs H/T Then adj ECF and Anti-Her2
LHT: pCR 51.3% in Breast and 47% in breast and LN (higher in ER neg)
GeparQuinto: Neoad EC/Doce + Herc or Tykerb
followed by adj Herc 50% pCR (more with Herceptin)
NeoSphere: Neoadj Doce +/- Pertuzumab +/-
Traztuzumab 3 drugs is better with 46% pCR; sig 40
Stage II-IIIA (T3N1)(Pt desires breast
preservation)1- Core biopsy of breast tumor + mark
tumor bed2- Axillary LN:
Clinically –ve Consider SLD
Clinically +ve Consider core Bx or FNA; if -ve Consider SLD
3- Then preop chemo/hormone: Any adj regimen or A.I. for postpenopausal or Trastuzumab-bsed therapy for her2-neu +ve
04/22/23 41
Stage II-IIIA (T3N1)(Pt desires breast
preservation)4- According to preop chemo response: Lumpectomy + LND (may omit if preop SLN –
ve) Mastectomy + LND (may omit if preop SLN –
ve)
5- Additional chemo in clinical trial6- Adj therapy may include:
RT Trastuzumab Hormonal therapy (could be given with
herceptin) Xeloda as radiosensitizer for high risk of
local recurrence (may give with herceptin)
04/22/23 42
Who is a candidate for adj. Systemic therapy?
Healthy Positive LN T >1 cm
(IDC or ILC)
T >3 cm (tubular, papillary, mucinous)
Data is limited for chemo in elderly (>70 yrs)
44
45
Chemotherapy
Chemo reduce mortality by 25% N+ =8% benefit N-ve.=2% benefit
Chemo reduce risk of recurrence by: 30% in pre menopausal 20% in post menopausal
Chemo reduce risk of death by: 25% in pre menopausal 15% in post menopausal
46
Anthracyclines Anthracycline vs non-Anthracycline:
12% proportional odd risk reduction of recurrence
11% odd risk reduction of death Absolute gain in survival;
4% in N+ve 1.7% in N-ve
Anthracycline benefits the most: Her2-neu +ve Topoisomerase lla +ve
48
CEF vs CMF
CEF-120 vs CMF: DFS; 62% vs 53% OS; 77% vs 70%
CEF: 29% risk reduction in recurrence 19% risk reduction in mortality
49
Intergroup (CALGB 93-44)3170 pts, node positive (18 m median
F/U)
AC AC T P DFS 86% + 1.2% 90% + 1.0% 0.0077 OS 95% + 0.7% 97% + 0.6% 0.0390
Improved DFS/OS from T but not from escalation of A dose. Taxol reduce recurrence rate by 22% and death rate by 26%
Henderson et al ASCO 1998 # 390A
51
NSABP B-28
AC Taxol: >3,000 N+ve pts)
Initial analysis: Benefits Receptors -ve pts Updates: Improves DFS & OS regardless of
receptors, use of tamoxifen, age or number of LNs
Taxol reduce DFS by 17%
Validates the CALGB 93-44
52
DOSE-DENSE
CALGB 9741 AC T (q2wk vs q3wk)
G-CSF support Dose-dense improves DFS
4Y DFS 82% vs 75% Benefit both ER status
53
Docetaxel + AC(High risk patients)
NSABP B-27 ECOG 2197 NSABP B-30
54
AC+Taxotere
TAX316 (Adj TAC vs FAC ) LN +ve TAC
improves DFS; sig improves OS
55
BCIRG 006
AC-Tere+/-Herceptin: Herceptin arm reduces risk of relapse by 51%
Taxotere/Carbo + Herceptin (TCH): reduces risk of relapse by 39% compared to
AC-T Lowe cardiac toxicity
No sig diff in risk of relapse between AC-TH and TCH
56
Adjuvant Herceptin(Over-expression of Her2-neu)
NSABP B-31 AC/Taxol AC/T q3wkx4 + Hx52
HERA standard adj chemo +/- H q3wk x12-24m
NCCTG 9831 AC/Taxol wkly x12 AC/Twkly x12 +concur Hx52 AC/Twkly x12 seq Hx40
57
Adj. Herceptin(NSABP_B31,NCCTG-N9831, HERA studies)
Joint analysis (NSABP_B31, NCCTG-N9831): Reduce overall risk of local recurr by 52% and
distant recurr by 53% @ 3yr CHF risk increased by 3-4%
HERA: Hercept sig improve DFS
46% reduction in recurrence
MUGA after AC, @ 6,9,18 m
58
Short course of Herceptin
FinHer trial: Doce or Nav +/- Herc X 9wks CEF
9 wk adj Herceptin + taxotere or navelbine is as effective as 52 wks Herceptin
No cardiac toxicity
59
Randomized Trials of Adj. HDCT
Negative Netherlands MD Anderson CALGB Scandinavian
? Positive S. African
60
ONCOTYPE DX Assay
Done on Formalin-fixed,Paraffin-embadded tumor tissue:
Gene panel (total of 21 genes) Proliferation set: ki67, etc ER set: ER, PR, Bcl2, SCUBE2 Invasion set: stromelysin 3,
cathepsin L2 Her2 set: Her2, GRB7 Other genes: BAG1, CD68
62
ONCOTYPE IN CLINICAL PRACTICE
Node negative ER positive: Scores out 100:
<18 = low risk (4-10% risk of distant recurrence) Treat with Tamoxifen
18-31 = intermed risk (8-20% risk of distant recurrence)
31-50 = high risk (24-37% risk of dist recurrence) Benefit from chemo
Node positive ER positive:63
Hormonal Therapy
Tamoxifen reduce risk of recurrence by 50% and risk of death by 30%
Do not give Hormonal therapy during Chemotherapy:
Risk of thromboembolism
64
Aromatase Inhibitors
Non-steroidal AI: Letrozole (Femara) Anastrazole (Arimidex)
Steroidal AI: Exemestane (Aromasin)
65
ATAC Adj study
Arimidex is superior to Tam in efficacy and tolerability.
17% improvement in DFS 60% vs 50% risk reduction in contral breast ca Less vaginal bleed/discharge, hot flashes, VTE Tam is better in fracture and musculoskeletal events
66
MA 17
Tam x 5yrs Letrozole x 5yrs reduce recurr in both N - & +ve reduce contralateral cancer Improve OS in N +ve pts only
67
Tam AI
IES study;- Tam x2-3yr Exemestine vs Tam x5yr
ABCSG/ARNO; Tamx2y ->AIx3
68
SYSTEMIC THERAPYSummary
Hormonal therapy improves survival irrespective of age and menopausal status
Polychemotherapy superior to monotherapy 12 months is not better than 6 months Additional benefit of chemo + HT in receptor +ve Anthracycline-regimen has better recurrence and
survival rates than CMF Ovarian ablation is comparable to chemotherapy to
reduce mortality in premenopausal
69
Risk Categories
Low Intermed High(All) (> 1)
LN -ve -ve +ve Tumor size < 1cm > 1-2cm > 2cm ER/PR +ve +ve -ve Grade 1 1-2 2-3 Age > 35 <35
71
Treatment: Node -ve
Low risk Intermed risk High risk Premenop Tamoxifen Chemo + Tam Chemo + Tam
ER/RP +ve ? Ov ablation ? Ov ablation
Premenop Chemo
ER/PR -ve
Postmenop Hormone Hormone or Chemo Chemo or
ER/PR +ve hormone
Postmenop Chemo
ER/PR -ve
72
Treatment: Node +ve
Premenop, ER/PR +ve Chemo + Tam? Ov ablation
Premenop, ER/PR -ve Chemo
Postmenop, ER/PR +ve Chemo or Hormones
Postmenop, ER/PR -ve Chemo73
75
•Ductal•Lobular•Mixed
•Metaplastic
Anthracycline benefits only; -Her2-neu +ve -topo ll +ve
ER/PR +
ER/PR -
Her2
+
Her2 -
Her2+
Her2
-
ER/PR +, Her2 +
ER/PR -, Her2 - (TN)
ER/PR +, Her2 -
ER/PR -, Her2 +
Herceptin in pts with small tumors (T1a-b), N-, Her2+
No enough data available Before use herceptin remember:
Toxicities (cardiac) Uncertain benefit in cohort
76
Adj Therapy of Favorable Histology
(Tubular, Mucinous/Colloid)
Usually ER +ve, Her2-neu –ve Medullary carcinoma should be
treated as other invasive ductal carcinoma
Prospective data regarding systemic adj therapy of favorable histology tumors are lacking
04/22/23 77
THANKS
78