Strategia terapeutica nella malattia avanzata Claudia Bighin Istituto Nazionale per la Ricerca sul Cancro Genova Roma, 19 Febbraio 2005

Metastatic Breast Cancer. The Big Picture 11,000 new cases/year of metastatic breast cancer in Italy 1,700 (15%) are ab initio metastatic patients Remaining patients are previously treated for early breast cancer

General Criteria to Select Patients for Endocrine or Chemo-therapy Endocrine Therapy Chemotherapy Slow-growing disease (soft tissue, skeleton) Rapidly growing disease (visceral involvement, skin limpang.) Long Disease Free Interval (>2 years) Short Disease Free Interval (< 2 years) Positive steroid hormone receptors Negative steroid hormone receptors Response to prior endocrine therapy Failure to first endocrine therapy Age >35 yearsAny age group Modified from Henderson, 1990 Cancer

General Criteria to Select Patients for Systemic Therapy Trastuzumab + Endocrinetherapy Trastuzumab + Chemotherapy Trastuzumab Alone 3+ by IHC Pos. by FISH (15%) All the Others (85%) HER 2 Status Endocrinetherapy Long DFS Age >35 years Response to prior endocrine therapy ER Positive/Ukn Slow-growing disease (soft tissue, skeleton) Chemotherapy Short DFS Any age group Failure to first endocrine therapy ER Negative Rapidly growing disease

Available Treatments for Metastatic Breast Cancer Endocrine therapy Chemotherapy Novel Biological Agents Surgery/RT -> isolated recurrence (Stage IV NED) Supportive Therapy

Available Treatments for Metastatic Breast Cancer Endocrine therapy Chemotherapy Novel Biological Agents Surgery/RT -> isolated recurrence (Stage IV NED) Supportive Therapy

Hormonal Agents for Breast Cancer SERMS Tamoxifen Toremifene LHRH analogs Aromatase Inhibitors Anastrozole Letrozole Exemestane Estrogens Estradiol DES Androgens Fluoxymesterone Progestins Megestrol Acetate MPA ER-Down Regulator Fulvestrant

Selective Estrogen Receptor Modulators First generation Toremifene, Droloxifene, Idoxifene Second /Third generation Raloxifene, Arzoxifene, EM-800, etc. Status: Advantage over Tam not shown

Third Generation Aromatase Inhibitors Trials vs. Tamoxifen Metastatic Setting Status: Advantage over Tam Neoadjuvant Setting Status: Advantage over Tam Adjuvant Setting Status: Advantage over Tam

Selected Second-line Randomized Phase III Trials with AI

Aromatase Inhibitors Versus Tamoxifen as First-Line Therapy in Metastatic Breast Cancer Anastrozole Letrozole Exemestane Patients, No.170 vs vs vs vs 189 OR, %21 vs 1733 vs 3330 vs vs 31 Clin. Benefit, %59 vs 4656 vs 5649 vs vs 49 TTP/PFS, mo11 vs 68 vs 89 vs 6 10 vs 6 ER unknown, %11 vs 1156 vs 5434 vs vs 11 Nabholtz et al. J Clin Oncol 18:3758, 2000; Bonneterre et al. J Clin Oncol 18:3748, 2000 Mouridsen et al. J Clin Oncol 19: 2596, 2001; Mouridsen et al. J Clin Oncol 21:2101, 2003; Paridaens et al. Proc ASCO 2004 Abs. 515

Neoadjuvant Randomized Phase III Trials with AI

1° linea ABC Adiuvante 2° linea ABC Neoadiuvante DCIS Prevenzione Inibitori dell aromatasi

Fulvestrant vs Anastrozole: 2nd line, after Tamoxifen StudyN° ptsMedian FU (mo) TTP (mo) OR (%) Osborne, JCO 02 Howell, JCO 02 Robertson, Cancer vs vs vs vs vs vs 16.5

Fulvestrant vs Tamoxifen: 1st line StudyN° ptsMedian FU (mo) TTP (mo) OR (%) Howell, JCO vs vs 33.9

Endocrine therapy in advanced pre-menopausal breast cancer Ovarian Ablation OA vs Tamoxifen Monotherapy vs Combination AI

Goserelin alone Meta-analysis of phase II studies: 200 pts Median survival: 26.5 months Overall RR: 36% (44% in ER+) Phase III study: Goserelin vs Oophorectomy: no difference in failure-free and overall survival Blamey, Eur J Cancer 1992 Taylor, JCO 1998

Randomized trials of OA vs Tamoxifen StudyPtsnTreatmentOutcome Ingle, JCO 86 Buchanan, JCO 86 Sawka, BCRT 97 HR+ or HR? Any HR HR+ or HR? OA (surg) vs T OA (surg) vs T OA (XRT/surg) vs T No diff Meta-analysis on 200 pts: no difference in RR, DFP or mortality Crump, BCRT 1997

Randomized trials of Monotherapy vs Combination StudyPtsnTreatmentOutcome Boccardo, Ann Oncol 94 Jonat, EJC 95 Klijn, JNCI 00 HR + or HR? Any HR HR + or HR? OA (XRT/surg) vs OA+T vs Z vs Z+T Z+T vs T B vs T vs B+T No diff No diff in OS PFS > with Z+T PFS and OS > with B+T Meta-analysis : combination > monotherapy for all end points Klijn, JCO 2001

AI in pre-menopausal breast cancer/1 Goserelin + Anastrozole in 16 advanced breast cancer as second line ET 75% objective response or SD Median duration of remission of 17 months (range 6-47) EstradiolFSH Forward, BJC 2004

AI in pre-menopausal breast cancer/2 Phase II study of Goserelin + Anastrozole 22 pre-menopausal recurrent or metastatic BC Objectives: ORR, CB, TTP, OS Toxicity Efficacy in suppression of plasma estradiol Preliminary resuts: PR: 22% (4); CR: 6% (1); SD: 44% (8); CB 72% Carlson, SABCS 2004

Available Treatments for Metastatic Breast Cancer Endocrine therapy Chemotherapy Novel Biological Agents Surgery/RT -> isolated recurrence (Stage IV NED) Supportive Therapy

Chemotherapy as First Choice. Drugs, Doses and Schedules Duration Integration of Chemotherapy and Endocrine therapy Integration of Chemotherapy and New Biological Agents

Metastatic Breast Cancer. Single Agents Grouped by Activity Modified from Chapter 36.2, 1996 De Vita et al.

Chemotherapy as First Choice. Drugs, Doses and Schedules Duration Integration of Chemotherapy and Endocrine therapy Integration of Chemotherapy and New Biological Agents

PolyCT with anthracycline vs no anthracycline

High vs low dose-intensive CT

Are anthracycline-taxane regimens the new standard of care in the treatment of metastatic breast cancer? Valero and Hortobagyi JCO 15 March 2003

Anthracycline-paclitaxel: phase III studies Study No.pts RandomOR % CR % TTPOS Jassem JCO A 50 P 220/3h F 500 A 50 C * * * Biganzoli JCO A 60 P 175/3h A 60 C Carmichael ASCO E 75 P 200/3h E 75 C Nr Luck ASCO E 60 P 175/3h E 60 C Nr * Statistical significant

Anthracycline-taxotere: phase III studies Study No.pts RandomOR % CR % TTPOS Nabholtz JCO A 50 T 75 A 50 C * * Mackey ASCO T 75 A 50 C 600 F 600 A 50 C * 7373 No diff Bonneterre BJC E 75 T 75 F 500 E 75 C * * 34 28* Bontenbal ECCO A 50 T 75 F 500 A 50 C * Nr * * * Statistical significant

PolyCT vs single agent

Poly vs. Monochemotherapy. Randomized Trials Anthra. vs. Anthra-based FEC vs E FEC-MV vs E-M FEC vs Mitoxantrone Doxo-Vin. vs Doxo Doxo-P vs Doxo Taxane vs. Non-Anthra CMFV vs P MV vs D MF vs D NF vs D Taxanes vs. Taxane-based D-Xeloda vs Docetaxel P-Gem vs Paclitaxel P-Doxo vs Paclitaxel

Poly vs. Monochemotherapy. Randomized Trials Anthra. vs. Anthra-based No difference in TTP, OS Similar activity Safety or QoL consistently favors monotherapy Doxo-Tax more active than doxo, but same OS Taxane vs. Non-Anthra Taxanes monoTx consistently better than non-anthra regimens Taxanes vs. Taxane-based Xeloda adds to docetaxel Gemcitabine adds to paclitaxel (survival?) Doxo adds to paclitaxel (same OS)

Poly vs. Monochemotherapy. Randomized Trials Anthracycline Monotherapy represents a reasonable option for most patients with metastatic breast cancer Taxotere 3-wk or Taxol weekly (Seidman, ASCO 04) monotherapy represents a reasonable option to anthracycline monotherapy Polychemotherapy in particular with taxane- anthracycline based regimens is especially suitable when response is the primary endpoint

Chemotherapy as First Choice. Drugs, Doses and Schedules Duration Integration of Chemotherapy and Endocrine therapy Integration of Chemotherapy and New Biological Agents

Appropriate Integration of Chemo / Endocrine Therapy Metastatic breast cancer patients Adjuvant breast cancer patients

CT and ET in patients candidates to both treatments Sequential treatment Concurrent treatment

Fossati R. et al. J Clin Oncol 10:3439, 1998 Concurrent chemotherapy and endocrine therapy

-> CT given 6-8 weeks after ET Concurrent vs Sequential Therapy

ET as Maintenance Therapy. Potential Advantages To prolong TTP without side effects of long-term CT Potential higher activity because of the low tumor burden (responding patients) Compared to concurrent administration, to avoid exposure and potential development of resistant clones in non- responding patients

Berruti et al. Anticancer Res 1997 ET as maintenance therapy after 1st line epirubicin

Available Treatments for Metastatic Breast Cancer Endocrine therapy Chemotherapy Novel Biological Agents Surgery/RT -> isolated recurrence (Stage IV NED) Supportive Therapy

Breast Cancer Metastases in Liver: Laser-induced Interstitial Thermotherapy , 232 patients (liver only or liver&bone; no. of mts < 6; Ø 5 cm) 45% both lobes involved 19% local unresectable tumor 8% recurrent after liver resection 3% general contraindication for surgery 25% refusal of surgery Median OS 4.3 yrs – 5-yr OS 41% Mack G et al. Radiology 233:400, 2004

Survival outcome in breast cancer patients with isolated metastases S.E. Singletary, The Oncologist 2003 Site of Metastases N° pts Treatment Survival Median (months) 5-year (%) 10 year (%) LUNG744S + CT + Tam42 – LIVER155S + CT NS BRAIN213S + RT + CT

Overall survival from time of recurrence 17 months 15 months 22 months 27 months 58 months SH Giordano, Cancer 2004