Brca mets

Elshami M. Elamin, MDMedical Oncologist

Central Care Cancer Centerwww.cccancer.comWichita, KS - USA

4% Melanoma of skin

4% Thyroid

27% Breast

15% Lung & bronchus

3% Kidney & renal pelvis

10% Colon & rectum

3% Ovary

6% Uterus

4% Non-Hodgkin’s lymphoma

3% Leukemia

23% All other sites

2% Brain

26% Lung & bronchus

15% Breast

6% Pancreas

9% Colon & rectum

5% Ovary

3% Uterus

4% Non-Hodgkin’s lymphoma

3% Leukemia

2% Liver & intrahepatic bile duct

25% All other sites

192,370 New Cases 40,170 Deaths

American Cancer Society. Cancer Facts & Figures 2009. Atlanta, GA: American Cancer Society; 2009.

CBC, Ca+, LFTs CEA, CA 27-29, CA 15-3 C-x-rays Bone scan Chest/Abd/Pelvis CT PET

4

Age, Menopausal status (at time of mets)

ER/PR, Her2 status Prior therapy and response Number/Sites of mets (<3, soft tissue/bone vs visceral)

PS Co-morbidity Psychosocial

5

Palliation: R.T. Hormonal therapy Chemotherapy Anti-her2 therapy Surgery

Prolong survival ? Cure

6

Routine surgerical removal of the primary tumor usually is not recommended !!

Only for local control and complications bleeding, ulceration, and infection at the

primary tumor site, "toilette" mastectomy

Survival is determined by distant mets, not by local disease

? No survival benefit ? May stimulate growth of mets

8

Elisabetta Rapiti, Helena M. Verkooijen, Georges Vlastos, Gerald Fioretta, Isabelle Neyroud-Caspar, André Pascal Sappino, Pierre O. Chappuis, Christine Bouchardy

J Clin Oncol 24:2743-2749, 2006

9

Geneva Cancer Registry (1977-1996)

Breast ca: Any T, any N, M1 = 317 pts (300 pts included in the study)

Compare mortality risks from breast ca between pts who had surgery of primary breast tumor to those had not.

population-based observational study

Not a randomized study

10

Local surgery No. of pts %

No surgery 173 58

Surg: -ve margins

61 20

Surg; +ve margins

33 11

Surg: margins unknown

33 11

Total 300 10011

Surgical removal of breast tumor improves prognosis of women with met breast cancer.

40% reduction in breast cancer mortality Only in pts with –ve margins

Sites of mets do not affect outcome. Pts with bone mets benefit the most

No significant survival benefit for axillary dissection

12

13

224 pts studied: 82 (37%) underwent mastectomy and 142 (63%) were treated without surgery. The median follow-up time was 32.1 months. Surgery was associated with a trend toward

improvement in overall survival (P=.12) and a significant improvement in metastatic progression-free survival (P=.0007)

14

Retrospective study of 16,023 patients. Surgery of the primary tumor was associated

with a 39% reduction in the risk of death 3 Yr Survival:

35% for patients excised to negative margins 26% for those with positive margins 17.3% for those not having surgery

(P < .0001).

No sig survival benefit for axillary dissection15

Women with metastatic breast cancer at diagnosis, primary tumor removal with negative margins significantly improves survival, especially in patients with only bone metastases.

Well-designed prospective studies are needed to re-evaluate the treatment paradigm "no surgery of the primary tumor" in breast cancer with metastases at diagnosis and to determine the impact of breast surgery on outcome of these patients.

16

New chemotherapy agents (Taxanes). Biologic agents.

Ant-Her2 (Herceptin, Tykerb) ? Avastin

Surgical complications are infrequent. In a multivariate analysis:

Each more recent year of recurrence was associated with a 1% per year reduction in the risk of death.

17

Response Time to Duration of

Rate % Response Response

Endocrine 30-40 2-3 mth 12-16 mth

Combination 50-70 1.5-2 mth 8-12 mth

Chemo

19

ER/PR Age Her-2 neu Sites of mets

Visceral/Bones

21

Tamoxifen (Novadex, Soltamox, Valodex, Istubal) Its metabolite hydoxytamoxifen acts as estrogen

antogonist in the breast It acts an estrogen agonist in the endometrium

Fulvestrant (Faslodex) Pure anti-estrogen (downregulates ER in breast

cancer cells)22

Premenopausal: Cause polycystic ovary (contraindicated)

Postmenopausal: Aromatization of adrenal androgens Estrogens ……

Aminoglutethemide Anastrozole (Arimidex) Letrozole (Femara) Exemestane (Aromasin)

23

Ovarian Ablation (Oophorectomy): Surgical (immediate) RT (2-3 months) LH-RH analogues

24

ER and/or PR +ve, Postmenopausal : Within one yr of antiestrogen:

A.Is. are preferred Antiestrogen naïve or more than 1 yr from

antiestrogen A.Is. appear superior compared to Tam

Recent Cochrane Review suggested small survival benefits

04/09/23 25

ER and/or PR +ve, Premenopausal: Within one yr of antiestrogen:

Ovarian ablation is preferred + endocrine therapy as postmenopaual

Antiestrogen naïve: Antiestrogen alone LHRH ovarian ablation + endocrine therapy as

postmenopaual

LHRH ovarian ablation + A.I. is not recommended

04/09/23 26

ER and/or PR +ve, Her2-neu +ve, Postmenopausal: Adding Trastuzumab or Lapatinib to A.Is.

Improves PFS

Anti-estrogen Fulvestrant is an option for: Postmenopausal after Tamoxifen or A.Is.

04/09/23 27

ER/PR negative Symptomatic visceral mets Receptor +ve refractory to endocrine

therapy

04/09/23 29

Paclitaxel (Taxol) T+Adria interfere with Adria metabolism

Cardiac toxicity High antitumor activity

ABRAXANE (Alb-bound Paclitaxel) (Cremophor-free)

Docetaxel (Taxotere/Adria) Improvement in RR/OS Febrile neutropenia

Navelbine, Capecitabine, Gemcitabine IXEMPRA (ixabepilone) Halaven (Eribulin):

anti-microtubules extracted from sea sponge

30

Predictive response Prior adjuvant chemo > 12 months Her-2 neu Topoisomerase IIa ? In vitro study

Prolong survival by ~ 20% MS : 20 – 30 months

31

Combination chemotherapy Higher ORR Longer TTP Increased toxicity Little survival benefit

04/09/23 32

Single-Agents (Adriamycin, Taxane, Xeloda, etc) Inferior to combination in RR and “survival” Recent studies

Similar survival Better QL Less toxicity

JCO 16:3720,1998

33

First-line (CMF, CAF, AC): RR 40-65% CR 10-15% Median Duration 10 months

2nd-line : RR < 30% CR < 10% Duration of response < 6 months

Adriamycin-Regimen: Statistically significant RR, Time to treatment failure, Survival More toxic (Alopecia, Myelosupression, Cardiotoxicity)

34

What is the optimal Duration of Chemo? ?6 cycles To maximum response or Stable dz 2-3 cycles beyond CR Chemo holiday

35

Conventional chemo vs High-dose chemo + ASCT No improvement in survival

Stadtmauer NEJM:2000

It is not a practice anymore

36

Med OS mth CHF AC 25 7% AC + Herceptin 33 27% T 18 1% T + Herceptin 22 12%

Chemo + Herceptin significantly better

Siamon ASCO 1998 #377, Norton ASCO 1999 # 483

38

ER/PR –ve: Trastuzumab alone or with Taxol +/- Carbo or Doce

or Vinorelbine or Capecitabine ER/PR +ve:

Trastuzumab with endocrine therapy Progression on Trastuzumzab:

Continue Trastuzumab Lapatinib +/- Capecitabine Lapatinib +/- Trastuzumab

Pertuzumab Trastuzumab-DM1

04/09/23 39

Met, advanced BC overexp Her2 s/p anthra, taxane, herceptin: Xeloda (2000mg/m qd)+/-Tykerb 1250mg (5tab) qd:

TTP 8.4 vs 4.4 m Toxiciy;

diarhea PPE cardiac 1.6% prolong QT

Dose reduce for; low LVEF hepatic

40

First-line Taxol +/- Avastin PFS 11.8 vs 5.9 m (P<0.001) No sig diff in OS

FDA revoked its indication

04/09/23 41

Locoregional

Systemic

43

Depends on: Type and extent of local/regional failure

Includes: RT Excision Endocrine therapy Chemotherapy Combinations

44

Initial treatment; Mastectomy or breast conservation:EORTC 10801 and Danish BCG 82TM trials (stage

I-II): No diff in initial events of local recurrences No diff in survival after salvage treatment

50% of both groups were alive at 10 yrs

Common sites of recurrence: If MRM and adj chemo without RT:

Chest wall and supraclavicular LN

04/09/23 45

After Mastectomy: Resection + IFRT if possible

After Breast conservation: Mastectomy and ALND if level I/II not previously done Limited data suggest that repeat SLND may be possible

Accuracy of repeat SLND is unproven

Small isolated in scar/skin flap Excision with 2-3 cm margin

04/09/23 46

NCCN:After lumpectomy/SLN:

•Mastectomy + level I/II ALND (preferred)•Consider SLN if prior axill staging done by SLN biopsy only

Axilla Resection if possible + RT

SCV RT

IM Node RT

47

After local treatment: Consider limited duration chemo or endocrine

therapy similar to adj therapy. BIG 101/IBCSG 27-02/NSABP B-37 [chemo for

isolated local and/or regional ipsil recurrence in early stage breast cancer]

04/09/23 48

Consider addition of hyperthermia to irradiation for local recurrence

No survival benefit

04/09/23 49

Treat as metastatic

50

Bisphosphonates (Pamidronate, Zoledronic acid)

Denosumab (XGEVA) Expected survival >3 months Adequate renal function Optimal duration not established Dental exam Calcium + Vit-D

51

52