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METASTATIC & Recurrent BREAST CANCER

Elshami M. Elamin, MD Medical Oncologist Central Care Cancer Center www.cccancer.com Wichita, KS - USA. METASTATIC & Recurrent BREAST CANCER. The Enormous Impact of Breast Cancer. 192,370 New Cases. 40,170 Deaths. 4% Melanoma of skin 4% Thyroid 27% Breast 15% Lung & bronchus

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METASTATIC & Recurrent BREAST CANCER

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  1. Elshami M. Elamin, MD Medical Oncologist Central Care Cancer Center www.cccancer.com Wichita, KS - USA METASTATIC & RecurrentBREAST CANCER

  2. The Enormous Impact of Breast Cancer 192,370 New Cases 40,170 Deaths 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 American Cancer Society. Cancer Facts & Figures 2009. Atlanta, GA: American Cancer Society; 2009.

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

  4. Prognostic & Treatment Selection Factors • 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. Goals of Treatment • Palliation: • R.T. • Hormonal therapy • Chemotherapy • Anti-her2 therapy • Surgery • Prolong survival • ? Cure

  6. is there any role of surgerical removal of the primary tumor?

  7. 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. Complete Excision of Primary Breast Tumor Improves Survival of Patients With Metastatic Breast Cancer at Diagnosis ElisabettaRapiti, Helena M. Verkooijen, Georges Vlastos, Gerald Fioretta, Isabelle Neyroud-Caspar, André Pascal Sappino, Pierre O. Chappuis, Christine Bouchardy J ClinOncol 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. Surgical Treatment

  11. RESULTS • 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. Effect of primary tumor extirpation in breast cancer patients who present with stage IV disease and an intact primary tumor.BabieraGV et alAnn SurgOncol. 2006 Jun;13(6):776-82. • 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)

  13. Does aggressive local therapy improve survival in metastatic breast cancer? 132:620-627, 2002(Khan SA, Stewart AK, Morrow M) • 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 dissection

  14. Surgical Treatment Conclusions • 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.

  15. CAN WE CURE METASTATIC BREAST CANCER ? • 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.

  16. TREATMENT

  17. OPTIONS OF SYSTEMIC THERAPY 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

  18. Endocrine Therapy

  19. Predictive response to hormonal therapy • ER/PR • Age • Her-2 neu • Sites of mets • Visceral/Bones

  20. Antiestrogens • 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)

  21. Aromatase Inhibitors • Premenopausal: • Cause polycystic ovary (contraindicated) • Postmenopausal: • Aromatization of adrenal androgens  Estrogens …… • Aminoglutethemide • Anastrozole (Arimidex) • Letrozole (Femara) • Exemestane (Aromasin)

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

  23. Endocrine Therapy • 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

  24. Endocrine Therapy • 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

  25. Endocrine Therapy • 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.

  26. Chemotherapy

  27. Cytotoxic chemotherapy • ER/PR negative • Symptomatic visceral mets • Receptor +ve refractory to endocrine therapy

  28. New Agents • 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

  29. CHEMOTHERAPY • Predictive response • Prior adjuvant chemo > 12 months • Her-2 neu • Topoisomerase IIa • ? In vitro study • Prolong survival by ~ 20% • MS : 20 – 30 months

  30. Cytotoxic chemotherapy • Combination chemotherapy • Higher ORR • Longer TTP • Increased toxicity • Little survival benefit

  31. CHEMOTHERAPY • 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

  32. Combination Therapy • 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)

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

  34. High-Dose Therapy • Conventional chemo vs High-dose chemo + ASCT • No improvement in survival Stadtmauer NEJM:2000 • It is not a practice anymore

  35. Immunotherapy

  36. Trastuzumab (Herceptin Med OS mth CHF • AC 25 7% • AC + Herceptin3327% • T 18 1% • T + Herceptin 22 12% • Chemo + Herceptin significantly better Siamon ASCO 1998 #377, Norton ASCO 1999 # 483

  37. Her2-targeted therapy • 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

  38. TYKERB, Lapatinib (EGFR and Her2 inhibitors) • 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

  39. Bevacizumab • First-line Taxol +/- Avastin • PFS 11.8 vs 5.9 m (P<0.001) • No sig diff in OS • FDA revoked its indication

  40. Recurrent disease

  41. Recurrent Disease • Locoregional • Systemic

  42. TREATMENT • Depends on: • Type and extent of local/regional failure • Includes: • RT • Excision • Endocrine therapy • Chemotherapy • Combinations

  43. Local recurrence • 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

  44. Local recurrence • 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 • NCCN: • After lumpectomy/SLN: • Mastectomy + level I/II ALND (preferred) • Consider SLN if prior axill staging done by SLN biopsy only

  45. Locoregional • Axilla • Resection if possible + RT • SCV • RT • IM Node • RT

  46. Local recurrence • 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]

  47. Hyperthermia • Consider addition of hyperthermia to irradiation for local recurrence • No survival benefit

  48. Systemic recurrence • Treat as metastatic

  49. Bone Mets • Bisphosphonates (Pamidronate, Zoledronic acid) • Denosumab (XGEVA) • Expected survival >3 months • Adequate renal function • Optimal duration not established • Dental exam • Calcium + Vit-D

  50. Thanks

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