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Breast cancer study group

Breast cancer study group. Outline. Adjuvant endocrine therapy Systemic disease Local disease Metastatic disease. Rationale for endocrine therapy of breast cancer. Estrogen and/or progesterone receptor expression is found in 85% of breast cancers. This proportion increases with age.

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Breast cancer study group

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  1. Breast cancer study group

  2. Outline Adjuvant endocrine therapy Systemic disease • Local disease • Metastatic disease

  3. Rationale for endocrine therapy of breast cancer • Estrogen and/or progesterone receptor expression is found in 85% of breast cancers. This proportion increases with age. Daidone MG, Coradini D, Martelli G, Veneroni S. Primary breast cancer in elderly women: biological profile and relation with clinical outcome. Crit Rev Oncol Hematol 2003;45:313–325

  4. 70%的乳癌有局部高度表現

  5. Adjuvant endocrine therapy Invasive cancer不論年齡、nodal status、HER2 status、要不要adjuvant chemotherapy，只要HR (+)就要用adjuvant endocrine therapy 誰不用endocrine therapy：<0.5cm且node (-)，或0.6-1.0cm合併favorable prognostic factor Side effect：hot flush、night sweat、osteoporosis (more in AI)、uterine cancer and DVT (more in tamoxifen)

  6. Agent history - tamoxifen • Initially developed in 1966. • Designed to be an oral contraceptive. • Actually induced ovulation. • Found to be at least equivalent to oopherectomy or CMF in 1986 and similar to megace with less toxicity in 1985 for metastatic disease.

  7. Tamoxifen – adjuvant tx Mortality From Any Cause Recurrence as First Event 100 100 91.8 Tamoxifen (~5 y) Tamoxifen (~5 y) 87.4 90 90 89.3 Control Control 78.9 79.2 80.1 80 80 74.9 Tamoxifen (~5 y) Tamoxifen (~5 y) Node -ve 73.3 Node -ve 70 70 75.6 Control Control 64.3 74.2 61.4 60 60 59.7 Node +ve 58.3 Node +ve % Alive 50 50 % Recurrence-free 50.5 40 40 44.5 30 30 Absolute Mortality Reduction Absolute Recurrence Reduction Node -ve: 5.6% SD 1.3: 2P<0.00001 Node +ve: 10.9% SD 2.5: 2P<0.00001 20 20 Node -ve: 14.9% SD 1.4: 2P<0.00001 Node +ve: 15.2% SD 2.5: 2P<0.00001 10 10 0 0 0 5 10+ 0 5 10+ Years Years Early Breast Cancer Trialists’ Collaborative Group. Lancet. 1998;351:1451.

  8. Aromatase inhibitor history • Aminoglutethimide was developed as an anti-epileptic and was shown to inhibit estrogen production in 1977. • Subsequently more specific and potent inhibitors have been developed. • The non-steroidal class reversibly bind the substrate binding site and the iron core. • The steroidal class irreversibly bind the substrate binding site.

  9. Adjuvant endocrine therapy AI：在functional ovary的病人無效，也不建議使用在因治療導致停經而無法準確評估卵巢功能的病人

  10. Extended adjuvant therapy • 5y tamoxifen is superior to 7y or 10y • Would further therapy with an AI improve outcomes? • MA-17 evaluated letrozole vs placebo for 5y after tamoxifen for 5y. • This trial has now been extended to evaluate an additional 5y of letrozole vs placebo

  11. 100 80 60 Percent P=0.00004 40 20 Femara Placebo 0 0 10 20 30 40 50 60 Time from randomization (months) No. at risk (Femara) 2583 2497 1905 1110 541 176 6 No. at risk (Placebo) 2587 2489 1874 1075 519 164 8 Risk of recurrence Goss P. [P1] The rise and current status of aromatase inhibitors in breast cancer treatment. The 27th Annual San Antonio Breast Cancer Symposium. San Antonio, TX.: Kluwer Academic Publishers; 2004.

  12. Primary endpoints at 2.5 years median follow-up

  13. Node-Positive Node-Negative 100 100 80 80 60 60 P=0.24 P=0.04 Percent 40 40 20 20 Femara Placebo Femara Placebo 0 0 0 10 20 30 40 50 60 0 10 20 30 40 50 60 Overall survival HR 0.61 months months

  14. RANDOMIZE Tamoxifen 2-3 y Tamoxifen2-3 y DFS/OS Exemestane 2-3 y • Companion Studies • Bone Metabolism (BMD) • Quality of life (FACT-ES) • Endometrial changes (TVUS) Milestones Activated March 1999 Planned accrual 4100 Actual accrual 4742 Should we switch earlier? Intergroup Exemestane Study IES Coombes R, Hall E, Snowdon C, Bliss J. [3] The Intergroup Exemestane Study: a randomized trial in postmenopausal patients with early breast cancer who remain disease-free after two to three years of tamoxifen-updated survival analysis. The 27th Annual San Antonio Breast Cancer Symposium. San Antonio, TX.: Kluwer Academic Publishers; 2004.

  15. Disease free survival at median follow-up 37.4 months 88.9 85.1

  16. Overall Survival at median follow-up 37.4 months

  17. Should we switch earlier? Probably The ABCSG 8 and ARNO trials used anastrozole for the switch and also show an improvement in DFS.

  18. Should we just start with AI? Anastrozole Tamoxifen And Combination Trial ATAC Schema: Anastrozole 1mg daily for 5y + placebo Or Tamoxifen 20mg daily for 5y + placebo Or Both anastrozole and tamoxifen for 5y (closed at first interim analysis due to equivalence to tamoxifen alone) Howell, A on behalf of the ATAC trialists group. ATAC (Arimidex, Tamoxifen, Alone or in Combination) completed treatment analysis: Anastrozole demonstrates superior efficacy and tolerability compared with tamoxifen. The 27th Annual San Antonio Breast Cancer Symposium. San Antonio, TX.: Kluwer Academic Publishers; 2004.

  19. DFS at median follow-up of 68 months • Anastrozole vs Hazard or Tamoxifen Population Odds Ratio 95% CI P Value • Disease-free survival ITT 0.87 0.78-0.97 0.01 HR+ 0.83 0.73-0.94 0.005 • Incidence of cBC ITT 0.58 0.38-0.88 0.01 HR+ 0.47 0.29-0.75 0.001 • Time to recurrence ITT 0.79 0.70-0.90 0.0005 HR+ 0.74 0.64-0.87 0.0002 • Time to distant ITT 0.86 0.74-0.99 0.04 recurrence HR+ 0.84 0.70-1.00 0.06 Howell, A on behalf of the ATAC trialists group. ATAC (Arimidex, Tamoxifen, Alone or in Combination) completed treatment analysis: Anastrozole demonstrates superior efficacy and tolerability compared with tamoxifen. The 27th Annual San Antonio Breast Cancer Symposium. San Antonio, TX.: Kluwer Academic Publishers; 2004.

  20. OS at median follow-up of 68 months 5y OS 84.3 % on anastrozole 83.8 % on tamoxifen P value = 0.7 No difference!

  21. Should we just start with AI? Most likely

  22. Tamoxifen 20 mg n=2446 Randomization Letrozole 2.5 mg n=2446 (Following complete tumor resection) Tamoxifen20 mg Letrozole n=1530 Letrozole 2.5 mg Tamoxifen n=1530 5 years 2 0 Enrollment completed • Primary End Points • Disease-free survival • Overall survival What order is best? Should we give tamoxifen at all? BIG 1-98 trial Thurlimann, B, Letrozole as adjuvant endocrine therapy for postmenopausal women with receptor-positive breast cancer. Conference at St. Gallens, 2005.

  23. DFS at median follow-up of 35.5 months

  24. 0.81 DFS 0.86 OS 0.83 SDFS 0.79 DFS (w/o 2nd malignancy) 0.73 Time to distant recurrence 0.72 Time to recurrence 0.5 0.75 1.0 1.33 2.0 Favors LET Favors TAM Hazard ratio (LET:TAM) OS at median follow-up of 35.5 months

  25. Adjuvant endocrine therapy 研究設計不同，對象不同，研究藥物也不同，所以沒有標準的initial、sequential、extend use of AI，使用的期間也未定論，但可確定的是不論是用在initial、sequential或extend，有用第三代AI的停經後病人都比只用tamoxifen的病人有更低的recurrence risk 除非病人有使用AI的contraindication，否則都不應只用tamoxifen

  26. ASCO guidelines for adjuvant therapy in HR + post-menopausal women • Optimal adjuvant therapy should include an AI as initial therapy or after treatment with tamoxifen in order to lower the risk of tumor recurrence • AIs are appropriate as initial treatment for women with contraindications to tamoxifen • For all other postmenopausal women, treatment options include 5 years of AI treatment or sequential therapy consisting of tamoxifen (for either 2-3 years or 5 years) followed by AIs for 2-3, to 5 years • Women with breast cancer and their physicians must weigh the risks and benefits of all therapeutic options

  27. Stage IV metastatic or recurrent breast cancer • Local disease • Systemic disease • Special consideration • Hx, PE, CBC/DC, LFT, CXR, bone scan • Plain film of painful bone or abnormal bone scan • Abdominal CT, MRI (optional) • HR status, HER2 status of lesions (if no previous data)

  28. Local disease s/p Mastectomy  surgical resection of local recurrence + R/T of involved field (no previous R/T or additional R/T may be safely administrated), limited excision with clear margin s/p BCS  total mastectomy Unresectable chest wall lesion: R/T if no previous R/T Hyperthermia + R/T: category 3, specialized expertise and equipment, no OS benefit

  29. Systemic disease Not curative! Prolong survival, improve QoL The least toxicity, the best choice! ± bone lesion  HR status and HER2 status

  30. Systemic disease Bisphosphonate When: if bone lesion (+), survival > 3months + Cr < 3.0mg/dl How: 3-5 weekly + Ca 1200-1500mg + Vit D3 400-800IU, last for 24 months What: Pamidronate 90mg for 2hrs, Zoledronic acid 4mg for 15mins No  OS, but  skeletal related events Monitor Cr, Ca, Mg, IP

  31. Systemic disease Osteonecrosis of jaw  the cumulative dose of drug,  the risk of osteonecrosis C/T, steroid, poor oral hygiene with periodontal disease and dental abscess preventive dentistry intervention, avoid dental procedure during treatment

  32. Systemic disease Not curative! Prolong survival, improve QoL The least toxicity, the best choice! ± bone lesion HR status and HER2 status Who to receive endocrine therapy: HR (+), HR (+) but refractory to prior endocrine therapy or HR (-) + bone or soft tissue only / asymptomatic visceral

  33. Aromatase inhibitors (AI) in the metastatic setting. • AI established as similar or superior to tamoxifen for metastatic disease in the early 1990’s.

  34. 2nd and 3rd line in metastatic disease • Switching class of AI or switching to direct ER inhibitor continues to produce clinical response.

  35. Systemic disease Endocrine therapy: Post menopausal with previous antiestrogen therapy and within 1 year of antiestrogen exposure  selective AI Post menopausal with antiestrogen naïve or > 1yr from antiestrogen therapy  AI superior to Tamoxifen

  36. Systemic disease Endocrine therapy: Premenopausal with previous antiestrogen therapy and within 1 year of antiestrogen exposure  surgical or radiotherappeutic oophorectomy or LHRH agonist + endodrine as postmenopausal women Premenopausal with antiestrogen naïve  antiestrogen ± LHRH agonist or ovarian ablation

  37. Systemic disease 只要有效就繼續用(SD、PR或CR)，沒效再換還是會有效果，且可合併其他治療方式 Fulvestrant：pure antiestrogen, monthly IM injection, longer duration of response than anastrozole Premenopausal的endocrine therapy與post-menopausal的差異：先用LHRH agonist、surgical or radio-oophorectomy讓病人停經！ 第二線以後的endocrine therapy沒有建議順序

  38. Systemic disease Cytotoxic chemotherapy： Who：HR(-) not localized in bone or soft tissue, symptomatic visceral involvement, HR (+) but refractory to endocrine therapy Combined regimen的response rate跟time to progression優於single agent，但side effect多且對OS沒有幫助，故不建議用combined regimen 一直打到progression跟打一段時間後休息等到progression相比，對於PFS有幫忙，但需考量諸如QoL等其他因素，不是一定要一直打。

  39. Systemic disease Single agent：doxorubicin、lipodox、epirubicin、taxol、docetaxol、capacitabine、vinorelbine、gemcitabine Combined regimen：FAC/CAF、FEC、AC、EC、AT、CMF Optional agent：ciplatin、carboplatin、etoposide (oral)、vinblastin 可以sequential use，與endocrine therapy一樣

  40. Systemic disease Bevacizumab：humanized monoclonal antibody against the bascular endothelial growth factor Ixabepilone：epothilone B analogue，單用 (2A)或併用capacitabine (2B)

  41. Targeting the Cancer Environment: Angiogenesis Inhibition Bevacizumab (Avastin) Anti-VEGF Antibody: binds to VEGF and blocks tumor blood vessel growth BLOOD VESSEL CELL VEGF Receptor VEGF Other VEGF/VEGFR inhibitors: sunitinib sorafenib CANCER CELL

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