Prof.Dr. Adnan Aydıner

İstanbul Üniversitesi Onkoloji Enstitüsü, İstanbul Tıp Fakültesi Tıbbi Onkoloji BD

www.adnanaydiner.com

Consider 10 Areas of Controversy

Surgery : Sentinel node

Radiation : DCIS, Accelerated, Partial, Post Mx

Pathology : ER, PgR, HER2, Ki-67, Grade

Multi-gene signatures

Endocrine therapies :esp. Over suppresion, Tamoxifen, AIs

Chemotherapies :esp. anthracyclines, taxanes, platin

Targeted therapies

Neo-adjuvant systemic therapy

Bisphosphonates

Male breast cancer

Response Key

Rejected [60% No]

Accepted [60% Yes]

???

Completion of axillary dissection is routinely indicated for patients with ITCs (isolated tumor cells) undergoing:

• Mastectomy Y %6 N %92 A %2

• BCT Y %0 N %93 A %7

The use of IHC to look for low volume disease in the sentinal lymph node is routinely indicated.

• Yes [Y] %22 No [N] %71 Abstention [A] %7

Surgical Therapy

Patients with clinically negative axilla should process to complete axillary dissection:

• If SLNB shows ITCs in marginal sinus and body of node

• Y %0 N %98 A %2

• If micrometastasis is less than 0,3 mm in a single SLN

• Y %4 N %91 A %4

• If there is metastasis of 0,2 – 2 mm in a single SLN

• Y %19 N %77 A %5

Surgical Therapy

The axillary recurrence rate in sentinel node-negative patients is 0.3%, which is well within the desired range.

Axillary recurrence after a tumour-negative sentinel node biopsy

Eur J Surg Oncol, 34(12):1277-84, 2008

The lowest recurrence rates were reported in

studies:

– performed in cancer centres,

– use (99m)Tc-sulphur colloid

– Use superficial injection technique or evaluated the

harvested sentinel nodes with haematoxylin-eosin

and immunohistochemistry staining

LN metastases of 2 mm or less vs LN with no metastases: OS

J Natl Cancer Inst 2010;102:410–425

For occult metastases: presence vs absence Poorer DFS RR = 1.55, 95% CI = 1.32 to 1.82) Poorer OS RR = 1.45, 95% CI = 1.11 to 1.88)

Axillary dissection vs no axillary dissection: OS

Cancer 115(8):1613-20, 2009

RT can be avoided in BCS for:

• Elderly (>70)

• Y %59 N %33 A %8

• Many low grade / low risk BCIS

• Y %62 N %32 A %6

RT should be considered standard for entirely excised DCIS in BCS

• Y %68 N %21 A %8

Radiation Therapy

Effect of surgical margin in patients receiving BCS + RT for DCIS

J Clin Oncol 27(10):1615-20, 2009

Negative margin reduced the recurrence

– Negative vs positive margins after RT (OR = 0.36; 95% CI, 0.27 to 0.47)

Negative margin reduced the risk of IBTR

– Negative vs close margins

OR=0.59 95%CI 0.42-0.83

– Negative vs unknown margin

OR=0.56 95%CI 0.36-0.87

Post-operative radiotherapy for DCIS

The Breast 18 (2009) 143–149

Benefit from the addition of radiotherapyon all ipsilateral:

– Breast events HR 0.49; 95%CI 0.41 to 0.58, p<0.00001

– Invasive recurrence HR 0.50; 95%CI 0.32 to 0.76, p=0.001

– DCIS recurrence HR 0.61; 95%CI 0.39 to 0.95, p=0.03

All the subgroups analysed benefited from addition of radiotherapy.

Accelerated whole BRT (WBRT) should be considered as an acceptable option (should be elaborate for whom?)

• Y %92 N %4 A %4

Radiation Therapy

In association with BCS, partial breast irradiation (intraoperative) is acceptable:

• As definitive irradiation without any external beam therapy

• Y %49 N %36 A %16

In association with BCS, partial breast irradiation (intraoperative) is acceptable:

• Instead of external beam boost to tumor bad

• Y %61 N %17 A %21

Radiation Therapy

Partial breast irradiation vs Whole breast radiation therapy

The Breast Journal, 16 (3):245–251, 2010

Survival

Values >1 indicate that partial breast irradiation has a worse outcome

Partial BRT should be applied in lymphoma survivors after mental field RT (including intraoperative):

• Y %37 N %26 A %37

Partial BRT should be applied in elderly (> age 70) (including intraoperative):

• Y %87 N %7 A %7

Radiation Therapy

Postmastectomy RT should recommended to all patients with N+ 1-3

• Y %18 N %71 A %11

Postmastectomy RT should be standard for patients with N+ ≥4:

• Y %88 N %5 A %7

Radiation Therapy

Postmastectomy RT should recommended to all patients with pT>2 cm

• Y %13 N %85 A %2

Radiation Therapy

Standard BRT should be preferred if extensive vascular invasion present.

• Y %35 N %33 A %33

Postmastectomy RT should recommended to all patients

• Only if young (under age 45)

• Y %51 N %42 A %7

• If with extensive vascular invasion (more than 2 blocks)

• Y %57 N %26 A %17

Radiation Therapy

The addition of radiotherapy resulted in: - 83% reduction in the risk of LRR (p< 0.00001) - 14% improvement in survival (p = 0.16)

RT to the chest wall following mastectomy for N (-)

Radiother Oncol 91(1):23-32, 2009

Baseline risk of locoregional relapse (LRR) is increased in the:

– presence of lymphovascular invasion

– a grade 3 tumour, greater than 2 cm or a close resection margin

– patients who are pre-menopausal or aged less than 50

For "Basal Like“ type use also CK5/6+ and/or EGFR+

• Y %7 N %81 A %12

Definition of subtypes of breast cancer use only readily available and reproducible pathological variables (ER, PR, Her-2, grade, Ki67)

• Y %91 N %9 A %0

Pathology

For "Luminal A“ use only ER+ and PgR+, HER2- and Ki67≤ %14 (low)

• Y %85 N %11 A %4

For "Luminal B“ use also ER+ PGR- and/or high Ki67 >14% and/or grade 3 with or without HER2+

• Y %51 N %36 A %13

Pathology

For “HER2+“ use only FDA definition (>%10 or >2)

• Y %68 N %23 A %9

For practical purposes tumor subtype can be ascertained by non-genetic tests for ER, PR, HER2 and Ki67

• Y %83 N %12 A %5

Choice of therapy depends on tumor subtype as defined by multigene array analysis

• Y %20 N %76 A %5

Choice of cytotoxic therapy should be influenced by tumor subtype

• Y %74 N %19 A %7

Pathology: Predictive factors

Mammoprint may be used to predict chemotherapy response in an endocrine responsive cohort

• Y %30 N %64 A %6

OncoTypeDX may be used to predict chemotherapy response in endocrine responsive cohort

• Y %84 N %11 A %4

Pathology: Multigene signatures

Standarts for premenapausal BC patients

Endocrine Therapy

Y N A

Tamoxifene alone 94 6 0

Ovarian function supression (OFS) + tamoxifene 83 12 5

OFS alone in all premenapausal ER+ patients 28 58 15

OFS alone (in extraordinary circumstances) 71 26 2

AIs plus OFS is a valid option in case of contraindication of tamoxifen 76 13 11

Standarts for postmenapausal BC patients

Endocrine Therapy

Y N A

All should receive AI 50 50 0

N+ should receive AI 79 21 0

Any should receive tamoxifene alone 89 11 0

AI need to be started first 41 52 7

Consider switch to tamoxifene in patients intolerate to AIs 98 0 2

5 years on AI is sufficient for low or moderate risk 81 12 7

More than 5 years AI should be offered to patients with:

N+ disease 34 55 11

Less than 55 years irrespectively of N status 5 86 9

AIs vs Tamoxifen: (A) recurrence (B) breast cancer mortality

J Clin Oncol 28:509-518, 2010

TamAIs vs Tam: (A) recurrence (B) breast cancer mortality

J Clin Oncol 28:509-518, 2010

Should the choice between AI and tamoxifene be dependent upon biological features (e.g N+, Ki67)

• Y %48 N %52 A %0

Patients receiving tamoxifene should have CYP2D6 testing

• Y %2 N %98 A %0

Endocrine Therapy

Should overexpressed or amplified HER2 be an indication of AI in postmenapausal

• Y %39 N %51 A %10

Should usually overexpressed or amplified HER2 be an indication for any ChT

• Y %84 N %13 A %3

Biologic Variables

Should obesity be considered a general contraindication of Aıs in postmenapausal patients

• Y %11 N %76 A %13

Factors arguing for inclusion of chemotherapy are:

Chemotherapy

Y N A

Histological grade 3 tumor 96 2 2

Ki67>14 69 15 17

Low hormone receptor status less than 50% 68 32 0

Positive HER2 status 96 4 0

Triple negative status 98 2 0

Any positive node 40 60 0

>3+ nodes 88 9 2

LVI 40 49 11

UPA may be used to select a chemotherapy (if not already indicated due to HER2-positive, etc.) in addition to endocrine treatment?

• Y %24 N %50 A %26

Where available, approved genetic testing such as Oncotype Dx or mammoprint may be used to select a chemotherapy (if not already indicated due to HER2-positive, etc.) in addition to endocrine treatment?

• Y %84 N %14 A %2

Chemotherapy

Chemotherapy regimens for luminal A or B

Chemotherapy

Y N A

For Luminal A phenotype:

Patients are less responsive to chemotherapy 86 5 9

Chemotherapy is less useful if added to endocrine therapy 85 0 15

There is a chemotherapy regimen known to be preferable 14 84 2

For Luminal B phenotype:

Should contain anthracyclines vs CMF 71 14 16

Should contain taxanes vs CMF 64 26 10

Chemotherapy regimens for HER2 (+):

Chemotherapy

Y N A

There is a chemotherapy regimen known to be preferred 37 59 4

The chemotherapy regimen may contain anthracyclines 98 2 0

The chemotherapy regimen should contain anthracyclines 74 23 2

The chemotherapy regimen should contain taxanes 83 11 7

Chemotherapy regimens for "basal like (triple negative breast cancer, infiltrating ductal cancer)" phenotype:

Chemotherapy

Y N A

Should contain anthracyclins and taxanes 82 13 4

Should contain platinum 18 64 18

Dose-dense chemotherapy should be considered 52 41 7

Antiangiogenic treatment should be added 2 88 10

Dose-dense chemotherapy vs conventional chemotherapy: OS

J Natl Cancer Inst 2010;102:1845–1854

Dose-dense chemotherapy vs conventional chemotherapy : DFS

A) Estrogen receptor–positive patients. B) Estrogen receptor–negative patients J Natl Cancer Inst 2010;102:1845–1854

Dose-dense chemotherapy vs conventional chemotherapy: Adverse events

A) All grade 3–4 adverse events. B) Grade 3–4 adverse events except leukopenia J Natl Cancer Inst 2010;102:1845–1854

Trastuzumab for 1 year with concurrent chemotherapy (usually a taxane) or following chemotherapy, is a standart adjuvant treatment for:

Chemotherapy

Y N A

HER2 positive phenotype 100 0 0

Tumors between 5 mm and < 1 cm? 79 12 6

Tumors pT1a 24 61 15

Transtuzumab treatment can be:

Shorter than 1 year in developed countries 26 63 12

Shorter than 1 year in underdeveloped countries 71 13 16

Longer than 1 year 5 84 12

Transtuzumab Schedule

Chemotherapy

Y N A

Should be given concurrently with chemotherapy 86 10 5

Could be initiated subsequently to chemotherapy rather than concurrently 84 9 7

If chemotherapy should be given, can be given alone 20 78 2

Trastuzumab alone (+/-endocrine therapy) is appropriate when

chemotherapy contraindicated 67 23 9

Neo-adjuvant therapy most-likely be given in order to alter the surgical outcome (chemo/endocrine trastuzumab)?

• Y %73 N %12 A %15

Neo-adjuvant therapy should be given only in order to alter the surgical outcome (less than mastectomy)

• Y %37 N %61 A %2

Neo-adjuvant Therapy

Neo-adjuvant chemotherapy is reasonable in highly endocrine-responsive disease (e.g. Lobular carcinoma, classical type)

• Y %19 N %77 A %14

Neo-adjuvant chemotherapy is reasonable for patients with low positive breast cancer index (e.g. Ki67 <14%)

• Y %24 N %64 A %12

Neo-adjuvant Therapy

If indicated, neo-adjuvant chemotherapy regimen should contain:

Neo-adjuvant Therapy

Y N A

Taxanes 83 9 9

Anthracyclines 89 7 4

Outside of clinical trials, should not contain unstandart regimen 86 12 2

For HER2 positive disease always should contain anti-her2 drug 87 9 4

Neo-adjuvant endocrine therapy alone is a reasonable option for postmenapousal patients with highly endocrine-responsive disease

• Y %98 N %2 A %12

Neo-adjuvant Therapy

15%

39%

46%

If y

es,

for

wh

ich

d

ura

tio

n?

3-4 months

4-8 months

Maximal response

Zoledronic acid shedule

Zoledronic acid

Y N A

Zoledronic acid, given during adjuvant endocrine therapy, should be

recommended to:

Premenapousal patients irrespective of OFS 10 81 8

Postmenapousal patients 21 72 6

Denosumab should substitute zoledronic acid 2 83 15

Zoledronic acid does given once every 6 months during adjuvant endocrine

therapy, improve DFS 23 65 13

For postmenapousal women 32 44 23

Does adjuvant bisphosphonate in early breast cancer modify the natural course of the disease?

Bisphosphonates vs no use

OR 95% CI p

– overall number of deaths 0.70 0.48-1.04 0.07

– bone metastases 0.92 0.76-1.11 0.41

– overall disease recurrences 0.84 0.60-1.18 0.32

– distant relapse 0.89 0.67-1.19 0.45

– visceral recurrences 1.05 0.68-1.60 0.82

– local relapses 1.05 0.75-1.48 0.75

Subgroup analyses: Zoledronic acid

– disease recurrence 0.67 0.47-0.95 0.02

J Natl Compr Canc Netw 2010;8:279-286

Until further evidence from new clinical trials becomes available, adjuvant bisphosphonates should not be recommended routinely

Treatment type

Male Breast Cancer Patients

Y N A

Adjuvant tamoxifen should be given to all male breast cancer patients 85 6 9

AI may be considered (If contraindication to TAM, e.g. Thrombosis) 54 33 14

An AI could be given in N(+) disease as extended endocrine treatment 28 44 30

If there is metastasis of 0,2 – 2 mm in a single SLN, patients should not routinely process to complete axillary dissection.

Conclusions

In association with BCS, partial breast irradiation (intraoperative) is not acceptable as definitive irradiation without any external beam therapy.

Postmastectomy RT should not be recommended to all patients with N(+)1-3.

Histological grade 3 tumor, Ki67>14, low hormone receptor status less than 50%, positive HER2 status, triple negative status, >3+ nodes, LVI are factors arguing for inclusion of CT.

Postmenopausal N+ or high risk patients should receive AIs.

For postmenapousal patients with highly endocrine-responsive disease neo-adjuvant endocrine therapy alone is a reasonable option. In responsive patients treatment duration should be more than 4 months.

Conclusions

Trastuzumab for 1 year with concurrent chemotherapy (usually a taxane) or following chemotherapy, is not a standart adjuvant treatment for tumors pT1a (<0.5 mm invazive tumour).

Zoledronic acid should not be recommended in the adjuvant treatment, except for some selected postmenopausal patients.

Prof.Dr. Adnan Aydıner

İstanbul Üniversitesi Onkoloji Enstitüsü, İstanbul Tıp Fakültesi Tıbbi Onkoloji BD

www.adnanaydiner.com