EARLY STAGE BREAST CANCER Operable local-regional inv cancer (Stage I, II, some IIIA)

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

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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

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STEROID RECEPTORS

The best use of ER/PR is not in determination of prognosis but in the

selection of optimal adjuvant systemic therapy

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Age

Young age is a significant predictor of local recurrence after breast conserving therapy

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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.

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Pathologic Factors

Histologic subtypes Histologic grade Nuclear grade Mitotic indix Vascular/lymphatic invasion Inflammatory response Tumor necrosis Mononuclear cell infiltration

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Biologic Factors

S-phase Ki 67 Her-2/neu Tumor supressor genes P53

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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

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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

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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

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Surgical Options

Breast conservation Lumpectomy + ALN staging

MRM + reconstruction

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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

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Re-excision of Primary

Indications: Extensive Intraductal Component (EIC)

especially with close margins (<2cm) Positive/uncertain margins Residual microcalcifications

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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

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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

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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

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Breast conservation(Lumpectomy + RT)

MRM: S% Lump/RT: S%

NSABP 60 62

EORTC 73 71

Danish 82 79

NCI 75 77

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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

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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

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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

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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

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NSABP B-27

Three arms:1. Preop AC local therapy2. Preop AC/Doce local therapy3. Preop AC local therapy Doce

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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

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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%

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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

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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)

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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)

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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

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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

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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

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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

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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

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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

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Docetaxel + AC(High risk patients)

NSABP B-27 ECOG 2197 NSABP B-30

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AC+Taxotere

TAX316 (Adj TAC vs FAC ) LN +ve TAC

improves DFS; sig improves OS

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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

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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

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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

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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

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Randomized Trials of Adj. HDCT

Negative Netherlands MD Anderson CALGB Scandinavian

? Positive S. African

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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

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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

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Aromatase Inhibitors

Non-steroidal AI: Letrozole (Femara) Anastrazole (Arimidex)

Steroidal AI: Exemestane (Aromasin)

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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

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MA 17

Tam x 5yrs Letrozole x 5yrs reduce recurr in both N - & +ve reduce contralateral cancer Improve OS in N +ve pts only

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Tam AI

IES study;- Tam x2-3yr Exemestine vs Tam x5yr

ABCSG/ARNO; Tamx2y ->AIx3

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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

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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

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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

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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

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•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

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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

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THANKS

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