Elżbieta Senkus-Konefka  Dept. of Oncology  and  Radi otherapy ,   Medical University of Gdańsk, Poland ESO Masterclass 20...
Neoadjuvant  therapy of breast cancer
<ul><li>POSSIBLE   </li></ul><ul><li>Earlier treatment of distant micrometastases </li></ul><ul><li>In vivo  sensitivity t...
Candidates for neoadjuvant therapy  <ul><li>LOCALLY ADVANCED or INFLAMMATORY BC </li></ul><ul><li>„ LARGE” OPERABLE BC </l...
Efficacy = adjuvant therapy Wolmark, JNCI Monogr 2001, Mauri, JNCI 2005
Other outcomes… mastectomy rate Mieog,  Br J Surgery 2007
no increase  in postoperative complications ? less cardiotoxicity and infections Mieog,  Br J Surgery 2007
but… Mauri, JNCI 2005   less aggressive local therapy  after tumor shrinkage  due to systemic therapy???
more recurrences in patients  with „downstaged” vs „preplanned” BCS Mieog,  Br J Surgery 2007
Who benefits from neoadjuvant treatment? Wolmark, JNCI Monogr 2001
Which patients benefit most? Colleoni, BCRT 2009   invasive ductal  carcinoma invasive lobular  carcinoma
Which patients benefit most? Huober, BCRT 2010
How important is pCR in relation  to other prognostic factors? Liedtke, JCO 2008
Can treatment results be improved? von Minckwitz, BCRT 2010   ?correlation with  long term outcomes
Is chemotherapy indispensable? Semiglazov, Cancer 2007
Is chemotherapy indispensable? Semiglazov, Cancer 2007
HTH  for  ER + Targeted therapy MD Anderson study Buzdar ,   JCO 2005 Trastuzumab  weekly   x 24 Paclitaxel q3w x 4 FEC x ...
Targeted therapy <ul><li>MD Anderson study </li></ul>pCR DFS Buzdar ,   JCO 2005,  Clin Cancer Res 2007
NOAH: trastuzumab in the neoadjuvant setting in ErbB2+ LABC Gianni ,  Lancet 2010 AP P CMF AP P CMF T + P T + CMF T contin...
NOAH: pathological complete response Gianni ,  Lancet 2010 0 10 20 30 40 50 With H Without H HER2 negative With H Without ...
NOAH study results  (HER2+) Gianni ,  Lancet 2010 0 6 12 18 24 30 36 Patients  Events  HR 95% CI p T + C T 1 17 18 0.62 0....
New targeted agents ↑ pCR ->  ??? long term outcome
Meaning of pCR <ul><li>surrogate for cure? </li></ul><ul><li>selection of best prognosis patients? </li></ul>will higher p...
Does pCR translate into long term outcome??? Gianni ,  Lancet 2010 EFS: HER2 +  (without trastuzumab)  vs HER2 - NOAH pCR ...
<ul><li>NSABP B-27 </li></ul>Does pCR translate into long term outcome??? Rastogi,   JCO  20 08 pCR rate DFS overall survi...
Metastatic breast cancer
… for metastatic breast cancer there are  few approved standards  of care…
 
(1) The management of metastatic breast cancer (MBC) is complex; therefore, involvement of all appropriate specialties in ...
Systemic management  of breast cancer supportive care chemo- therapy hormono- therapy targeted  therapy
(2) From the first diagnosis of MBC, patients should be offered personalised appropriate psychosocial, supportive, and sym...
disease  and treatment sequelae antiemetics colony-stimulating factors bisphosophonates analgesics psychotropics
(3) Following thorough  assessment and  confirmation of MBC, the realistic treatment goals must be specified and discussed...
Primary goals in the treatment of MBC <ul><li>Maintenance of  quality of life and function </li></ul><ul><li>Reduction of ...
Management of Advanced Breast Cancer: Efficacy vs   Toxicity
(4) A small but very important subset of MBC patients, for example, those with a solitary metastatic lesion, can achieve c...
Is MBC curable? <ul><li>RATIONALE:   in the era of improved systemic control with new therapies a removal of intact primar...
Surgery for primary in MBC? 0.67   ND   5179/9197  (56.3%)   Khan 2003  0.53   surgery: 26.8 no surgery: 12.6   187/409  (...
Surgery for primary in MBC? 0.67   ND   5179/9197  (56.3%)   Khan 2003  0.53   surgery: 26.8 no surgery: 12.6   187/409  (...
Surgery for primary in MBC? Rapiti, JCO 2006 only  selection  bias?
Resection of metastases? <ul><li>467 cases of the international registry of lung metastases </li></ul>Friedel , Eur J Card...
(5) Minimal staging work-up for MBC includes a history and physical examination, complete haematology and biochemistry, an...
(5) – contd. The clinical value of tumour markers is not well established for diagnosis or follow-up; however, their use a...
Should we rebiopsy the tumor? Liedtke, Ann Oncol 2009
Should we rebiopsy the tumor? Liedtke, Ann Oncol 2009, Wilking 2011 biology  or suboptimal treatment???
(6) <ul><li>Treatment choice should take into account: </li></ul><ul><li>endocrine responsiveness,  </li></ul><ul><li>HER-...
systemic  treatment  of breast cancer previous treatments anthracycline dose taxane use late sequelae tumor organ  involve...
(7) Endocrine therapy is the  preferred option  for hormonal receptor-positive disease, unless there is concern or proof o...
<ul><li>For  pre-menopausal  women,  tamoxifen combined with ovarian suppression/ablation is the first choice  except for ...
The optimal first-line hormonal treatment for  postmenopausal  patients is an  aromatase inhibitor ; however,  tamoxifen  ...
<ul><li>Maintenance of hormonal treatment after chemotherapy is not established, but is reasonable.  </li></ul><ul><li>Con...
(8) Trastuzumab should be offered early to all HER-2-positive MBC patients,  either combined with chemo or endocrine thera...
Trastuzumab + chemotherapy Slamon, NEJM 2001 H0648g  study probability of survival 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1...
Trastuzumab + chemotherapy DFS Marty ,   J Clin Oncol.  2005 overall survival M77001  study Docetaxel + trastuzumab Doceta...
Trastuzumab + chemotherapy  –  subgroup analysis Marty, JCO 2005 M77001  study 0.1 1 10 100 Docetaxel better Trastuzumab  ...
time-to-progression Di Leo, ASCO 2007 Lapatinib – I line treatment p=0.007
overall survival Lapatinib – I line treatment Di Leo, ASCO 2007
Anti-HER2 therapy  in combination  with  endocrine therapy   is superior to endocrine therapy alone  for  HER-2 positive/E...
ER – HER2 crosstalk Arpino ,  Endocr Rev 2008
73 / 104  patients  (70%)  were crossed-over to trastuzumab  on progression 0.4 PFS Mackey, SABCS 2006  Trastuzumab + horm...
Trastuzumab + hormonotherapy Overall survival for patients on T + A vs A,  excluding patients who crossed over to T Kaufma...
Lapatinib + letrozole Johnston ,  JCO 2009 HR-positive, HER2-positive patients PFS overall survival
Lapatinib + letrozole Johnston ,  JCO 2009 HER2(–) patients with <6 months since discontinuation of adjuvant tamoxifen
Patients progressing on an anti-HER-2 therapy  combined with a cytotoxic agent  should be offered a  second combination of...
GBG-26 Von Minckwitz,  JCO 2009 Continuing trastuzumab beyond progression… capecitabine   + trastuzumab   (n=78) MBC HER2 ...
Continuing trastuzumab beyond progression… 54.0% 75.3% 27.0% 48.0% CR + PR   p = 0.011 clinical benefit   p = 0.0068 Von M...
Von Minckwitz,  JCO 2009 Continuing trastuzumab beyond progression… PFS 40 0 0.0 0.2 1.0 0.8 0.6 0.4 10 20 30 HR=0.69   p=...
Trastuzumab resistance <ul><li>p95 ErbB2  ~ 30% HER2 (+) breast cancers </li></ul>
Targets for anti-HER2 compounds trastuzumab lapatinib
Lapatinib  – active in  p95 ErbB2 (+) tumors Scaltriti ,   J NCI  2007
Scaltriti, Clin Cancer Research 2010 Lapatinib  – active in  p95 ErbB2 (+) tumors Lapatinib +capecitabine
EGF100151 Cameron,  BCRT  2008 , Oncologist 2010 Lapatinib – post trastuzumab failure overall survival (weeks) time-to-pro...
PFS  ( weeks ) Blackwell, JCO 2010 Combining targeted therapies…
Combining targeted therapies… Blackwell, JCO 2010 OS  ( weeks )
(9) Both  combination  and  sequential single agent monotherapy  are reasonable first-line chemotherapy options.  I n the ...
(9) – contd. Patient- and disease-related factors should be used to choose between combination and sequential single-agent...
Median  PFS/TTP (mths) Combination vs single agent?   Pacilio 2006 9 months 0 2 4 6 8 10 Mu-oz 2006 Zielinski 2005 Albain ...
Combination vs single agent?   m edian OS  (mths) O’Shaughnessy 2002 Melemed 2007 Sledge 2003 Seidman 2004 Jones 2005 24 m...
Combination vs single agent? <ul><li>E1193 </li></ul>Sledge,   JCO 2003 doxorubicin vs paclitaxel vs doxo + paclitaxel tim...
Combination vs single agent?   randomized studies with planned cross-over Cardoso,   JNCI 2009
Optimal therapy choice? <ul><li>monotherapy </li></ul><ul><ul><li>slow natural history </li></ul></ul><ul><ul><li>older ag...
<ul><li>in the past </li></ul>Chemotherapy – paradigm change now progression progression progression
Duration of chemotherapy Gennari,   ESMO 2010
(10) There are few proven standards of care in MBC management. Therefore, inclusion of patients in well-designed, independ...
(11) The medical community is aware of the problems raised by the cost of MBC treatment. Balanced decisions should be made...
Bewacizumab <ul><li>E2100 – progression free survival </li></ul>Miller,  NEJM  200 7 0 20 40 60 80 100 Time (months) Progr...
Bewacizumab Miller,  NEJM  200 7 E2100 – overall survival no effect on survival!!! Months 1.0 0.8 0.6 0.4 0.2 0 HR=0.869  ...
Bewacizumab AVADO – progression free survival Mile s ,  ASCO 2008 BEV 7.5 mg/kg BEV 15 mg/kg Median 8.0  vs 8.7 mths HR 0 ...
(12) Formal (not just informal) quality of life assessments provide useful information and should be encouraged. If collec...
Difficult issues triple-negative breast cancer
Inhomogenous disease „ triple negative” BC basal-like BC BRCA1 -related BC no single treatment  is going to be effective  ...
Choice of ChT <ul><li>anthracyclines? </li></ul><ul><ul><li>theory – ideal compounds </li></ul></ul><ul><ul><ul><li>freque...
Anthracyclines? <ul><li>clinical data conflicting </li></ul>Di Leo, SABCS 2008, Cheang ,  ASCO 2009 NCIC-CTG MA5 A better ...
Choice of ChT <ul><li>taxanes? </li></ul><ul><ul><li>theory </li></ul></ul><ul><ul><ul><li>80% of TNBC are p53 mutant – po...
Taxanes? <ul><li>clinical data conflicting </li></ul>Hayes, NEJM 2007, Ellis, Lancet 2009 CALGB 9344 all patients N+ patie...
Choice of ChT <ul><li>platinum? </li></ul><ul><ul><li>theory </li></ul></ul><ul><ul><ul><li>platinum  -> double strand DNA...
Byrski, JCO 2010 Neoadjuvant treatment of 102 consecutive BRCA1 (+) breast cancer pts 83% 10 12 Cisplatin 8% 2 25 AT 21% 6...
Platinum in TNBC <ul><li>few prospective data exist </li></ul><ul><li>metronomic cyclophosphamide and methotrexate   ±   c...
<ul><li>synthetic lethality </li></ul>PARP-inhibitors Wild BRCA DNA damage BRCA PARP DNA repair DNA damage BRCA PARP DNA r...
PARP-inhibitors O’Shaughnessy ,  NEJM 2011 „ triple negative„  BC 0–2 prior chemotherapy regimens for MBC
 
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MON 2011 - Slide 4 - E. Senkus-Konefka - Treatment of metastatic disease and neoadjuvant therapy

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  • 5 Neoadjuvant treatment
  • The NeOAdjuvant Herceptin Study (NOAH) was an international phase III trial evaluating the efficacy and safety of chemotherapy with an anthracycline and taxane, followed by cyclophosphamide, methotrexate and 5-fluorouracil (CMF), with or without trastuzumab, in women with newly diagnosed locally advanced breast cancer ( LABC) 1 . The design of the study provided the opportunity to compare the results of the same chemotherapy regimen without trastuzumab in a parallel cohort of women with ErbB2-negative breast cancer. In this multicentre, randomised, open-label trial, women with ErbB2+ (IHC 3+ or FISH+) LABC were randomised to receive 3 cycles of doxorubicin (60 mg/m) and paclitaxel (150 mg/m) every 3 weeks, 4 cycles of paclitaxel (175 mg/m every 3 weeks) and 3 cycles of CMF (cyclophosphamide 600 mg/m, methotrexate 40 mg/m, 5-fluorouracil 600 mg/m every 4 weeks) on days 1 and 8, with or without concomitant trastuzumab (8 mg/kg loading dose then 6 mg/kg every 3 weeks for 1 year) before surgery. In parallel, LABC patients screened as ErbB2-negative (IHC 0/1+) received the same chemotherapy regimen. The primary end point was event-free survival (EFS), defined as the time between randomisation and disease recurrence or progression, or death from any cause. Secondary endpoints were pathological complete response (pCR), overall response rate (ORR), overall survival (OS) and safety. Gianni L, et al. Neoadjuvant trastuzumab in patients with HER2-positive locally advanced breast cancer: primary efficacy analysis of the NOAH trial. SABCS 2008 (Dec); Abstract 31 5 Neoadjuvant treatment
  • 327 patients were enrolled in NOAH. Inflammatory breast cancer was present in 27% of ErbB2+ vs. 14% of ErbB2-negative tumours, while 35% vs. 64%, respectively, were hormone-receptor positive. In this prospective intent-to-treat analysis, the pCR rate for ErbB2+ patients was 43% when trastuzumab was added to chemotherapy, and 23% in the control arm (p=0.002); of note, the same chemotherapy regimen yielded a 17% pCR in ErbB2-negative patients (p=ns). Gianni L, et al. Neoadjuvant trastuzumab in patients with HER2-positive locally advanced breast cancer: primary efficacy analysis of the NOAH trial. SABCS 2008; Abstract 31 and presentation pCR and tpCR
  • Event-free survival (EFS) was analysed after 88 events in the ErbB2+ group (n=228). EFS rate at 3 years was significantly better in the trastuzumab arm (70.1%) compared with chemotherapy alone (53.3%, hazard ratio [HR] 0.56; p=0.007). EFS rate in the ErbB2-negative arm was 67.4%. The addition of trastuzumab to chemotherapy in the neoadjuvant setting was well tolerated, with acceptable cardiac safety. The authors concluded that neoadjuvant trastuzumab significantly increased EFS in patients with ErbB2+ LABC, establishing neoadjuvant trastuzumab with chemotherapy as a standard treatment option in women with ErbB2+ LABC. Gianni L, et al. Neoadjuvant trastuzumab in patients with HER2-positive locally advanced breast cancer: primary efficacy analysis of the NOAH trial. SABCS 2008; Abstract 31 and presentation 5 Neoadjuvant treatment
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  • Herceptin combination Docetaxel Breast cancer: metastatic-first line Breast cancer: metastatic Trial Pivotal trial Response Efficacy
  • citation
  • znamienność?????
  • Transcript of "MON 2011 - Slide 4 - E. Senkus-Konefka - Treatment of metastatic disease and neoadjuvant therapy"

    1. 1. Elżbieta Senkus-Konefka Dept. of Oncology and Radi otherapy , Medical University of Gdańsk, Poland ESO Masterclass 2011 15th century painting in Santa Maria della Grazia in Milan Breast cancer - neoadjuvant therapy and t reatment of metastatic disease
    2. 2. Neoadjuvant therapy of breast cancer
    3. 3. <ul><li>POSSIBLE </li></ul><ul><li>Earlier treatment of distant micrometastases </li></ul><ul><li>In vivo sensitivity test of systemic agents </li></ul><ul><li>Improvement of survival vs. local therapy alone </li></ul><ul><li>PROVEN </li></ul><ul><li>Improved operability rates of initially inoperable tumors </li></ul><ul><li>Improved rates of breast-conserving surgery </li></ul><ul><li>Translational correlative studies </li></ul>POSSIBLE DISADVANTAGES T umour progression i f no response to systemic therapy Loss of pathological prognostic information ADVANTAGES
    4. 4. Candidates for neoadjuvant therapy <ul><li>LOCALLY ADVANCED or INFLAMMATORY BC </li></ul><ul><li>„ LARGE” OPERABLE BC </li></ul>Primary systemic therapy = treatment of choice Primary systemic therapy = option
    5. 5. Efficacy = adjuvant therapy Wolmark, JNCI Monogr 2001, Mauri, JNCI 2005
    6. 6. Other outcomes… mastectomy rate Mieog, Br J Surgery 2007
    7. 7. no increase in postoperative complications ? less cardiotoxicity and infections Mieog, Br J Surgery 2007
    8. 8. but… Mauri, JNCI 2005 less aggressive local therapy after tumor shrinkage due to systemic therapy???
    9. 9. more recurrences in patients with „downstaged” vs „preplanned” BCS Mieog, Br J Surgery 2007
    10. 10. Who benefits from neoadjuvant treatment? Wolmark, JNCI Monogr 2001
    11. 11. Which patients benefit most? Colleoni, BCRT 2009 invasive ductal carcinoma invasive lobular carcinoma
    12. 12. Which patients benefit most? Huober, BCRT 2010
    13. 13. How important is pCR in relation to other prognostic factors? Liedtke, JCO 2008
    14. 14. Can treatment results be improved? von Minckwitz, BCRT 2010 ?correlation with long term outcomes
    15. 15. Is chemotherapy indispensable? Semiglazov, Cancer 2007
    16. 16. Is chemotherapy indispensable? Semiglazov, Cancer 2007
    17. 17. HTH for ER + Targeted therapy MD Anderson study Buzdar , JCO 2005 Trastuzumab weekly x 24 Paclitaxel q3w x 4 FEC x 4 Paclitaxel q3w x 4 FEC x 4 n=23 n=19 Stage II Her2 + IHC 3+ / FISH +
    18. 18. Targeted therapy <ul><li>MD Anderson study </li></ul>pCR DFS Buzdar , JCO 2005, Clin Cancer Res 2007
    19. 19. NOAH: trastuzumab in the neoadjuvant setting in ErbB2+ LABC Gianni , Lancet 2010 AP P CMF AP P CMF T + P T + CMF T continued R n= 1 15 n=99 n= 1 13 Surgery + RT Surgery + RT Surgery + RT T + AP ErbB2 ( + ) ErbB2 ( - )
    20. 20. NOAH: pathological complete response Gianni , Lancet 2010 0 10 20 30 40 50 With H Without H HER2 negative With H Without H HER2 negative Patients, % HER2 positive HER2 positive BREAST ONLY BREAST AND NODES 43% 22% 17% 38% 19% 16% p=0.37 p=0.002 p=0.003 p=0.43
    21. 21. NOAH study results (HER2+) Gianni , Lancet 2010 0 6 12 18 24 30 36 Patients Events HR 95% CI p T + C T 1 17 18 0.62 0.34–1.23 0.11 C T 1 18 26 0.25 0.50 0.75 1.00 0.00 Months Patients Events HR 95% CI p T + C T 1 17 36 0.59 0.36–0.85 0.013 C T 1 18 51 0 6 12 18 24 30 36 42 0.25 0.50 0.75 1.00 Overall survival 0.00 Months 42 Event-free survival Probability, EFS Probability, overall survival
    22. 22. New targeted agents ↑ pCR -> ??? long term outcome
    23. 23. Meaning of pCR <ul><li>surrogate for cure? </li></ul><ul><li>selection of best prognosis patients? </li></ul>will higher pCR rate translate into improved long term outcome?
    24. 24. Does pCR translate into long term outcome??? Gianni , Lancet 2010 EFS: HER2 + (without trastuzumab) vs HER2 - NOAH pCR rates 1.00 0.75 0.50 0.25 0.00 0 6 12 18 24 30 36 42 Probability, EFS Months CT, HER2 + CT, HER2 - 0 10 20 30 40 50 With H Without H HER2 - With H Without H HER2 - Patients, % HER2 + HER2 + BREAST ONLY BREAST AND NODES 43% 22% 17% 38% 19% 16% p=0.37 p=0.002 p=0.003 p=0.43
    25. 25. <ul><li>NSABP B-27 </li></ul>Does pCR translate into long term outcome??? Rastogi, JCO 20 08 pCR rate DFS overall survival
    26. 26. Metastatic breast cancer
    27. 27. … for metastatic breast cancer there are few approved standards of care…
    28. 29. (1) The management of metastatic breast cancer (MBC) is complex; therefore, involvement of all appropriate specialties in a multi/interdisciplinary team (medical, radiation, surgical and imaging oncologists, palliative care, psycho-social, among others) is crucial.
    29. 30. Systemic management of breast cancer supportive care chemo- therapy hormono- therapy targeted therapy
    30. 31. (2) From the first diagnosis of MBC, patients should be offered personalised appropriate psychosocial, supportive, and symptom-related interventions as a routine part of their care.
    31. 32. disease and treatment sequelae antiemetics colony-stimulating factors bisphosophonates analgesics psychotropics
    32. 33. (3) Following thorough assessment and confirmation of MBC, the realistic treatment goals must be specified and discussed. Patients and family members should be invited to participate in all decision-making.
    33. 34. Primary goals in the treatment of MBC <ul><li>Maintenance of quality of life and function </li></ul><ul><li>Reduction of cancer related symptoms and complications </li></ul><ul><li>Prolongation of survival </li></ul>
    34. 35. Management of Advanced Breast Cancer: Efficacy vs Toxicity
    35. 36. (4) A small but very important subset of MBC patients, for example, those with a solitary metastatic lesion, can achieve complete remission and a long survival. For these selected patients, a more aggressive and multidisciplinary approach should be considered .
    36. 37. Is MBC curable? <ul><li>RATIONALE: in the era of improved systemic control with new therapies a removal of intact primary or oligometastatic foci may prevent further tumor spread and allow for long-term disease control </li></ul>
    37. 38. Surgery for primary in MBC? 0.67 ND 5179/9197 (56.3%) Khan 2003 0.53 surgery: 26.8 no surgery: 12.6 187/409 (45.7%) Fields 2007 0.5 not reached predicted: 54 82/224 (37%) Babiera 2006 Rao 2008 0.71 surgery: 27.1 no surgery: 16.8 242/395 (61.3%) Blanchard 2008 0.63 surgery: 27 no surgery: 12 4578/9734 (47%) Gnerlich 2007 margin (-): 0.6 margin (+): NS margin (-): 26 margin (+): 17 no surgery: 13 127/300 (42%) Rapiti 2006 margin (-): 0.61 margin (+): 0.75 total mastectomy: 31.9 partial mastectomy: 26.9 no surgery: 19.3 9162/16023 (57.2%) Khan 2002 HR for OS (surgery vs not) median OS (months) N° patients: operated/all (%) Author
    38. 39. Surgery for primary in MBC? 0.67 ND 5179/9197 (56.3%) Khan 2003 0.53 surgery: 26.8 no surgery: 12.6 187/409 (45.7%) Fields 2007 0.5 not reached predicted: 54 82/224 (37%) Babiera 2006 Rao 2008 0.71 surgery: 27.1 no surgery: 16.8 242/395 (61.3%) Blanchard 2008 0.63 surgery: 27* no surgery: 12* 4578/9734 (47%) Gnerlich 2007 margin (-): 0.6 margin (+): NS margin (-): 26* margin (+): 17* no surgery: 13* 127/300 (42%) Rapiti 2006 margin (-): 0.61 margin (+): 0.75 total mastectomy: 31.9 partial mastectomy: 26.9 no surgery: 19.3 9162/16023 (57.2%) Khan 2002 HR for OS (surgery vs not) median OS (months) N° patients: operated/all (%) Author
    39. 40. Surgery for primary in MBC? Rapiti, JCO 2006 only selection bias?
    40. 41. Resection of metastases? <ul><li>467 cases of the international registry of lung metastases </li></ul>Friedel , Eur J Cardio-Thor Surg 2002
    41. 42. (5) Minimal staging work-up for MBC includes a history and physical examination, complete haematology and biochemistry, and imaging of the chest, abdomen and bone.
    42. 43. (5) – contd. The clinical value of tumour markers is not well established for diagnosis or follow-up; however, their use as an aid to evaluate response to treatment, particularly in patients with nonmeasurable disease, is acceptable.
    43. 44. Should we rebiopsy the tumor? Liedtke, Ann Oncol 2009
    44. 45. Should we rebiopsy the tumor? Liedtke, Ann Oncol 2009, Wilking 2011 biology or suboptimal treatment???
    45. 46. (6) <ul><li>Treatment choice should take into account: </li></ul><ul><li>endocrine responsiveness, </li></ul><ul><li>HER-2 status, </li></ul><ul><li>menopausal status, </li></ul><ul><li>disease-free interval, </li></ul><ul><li>previous therapies and response obtained, </li></ul><ul><li>tumour burden (defined as number and site of metastases), </li></ul><ul><li>biological age and co-morbidities (including organ dysfunctions), </li></ul><ul><li>performance status, </li></ul><ul><li>need for rapid disease/symptom control, </li></ul><ul><li>socio-economic and psychological factors, </li></ul><ul><li>patient’s preference </li></ul><ul><li>and available therapies in the patient’s country (this list is not exhaustive). </li></ul>
    46. 47. systemic treatment of breast cancer previous treatments anthracycline dose taxane use late sequelae tumor organ involvement biology tumor bulk patient age performance status co-morbidities clinical trial ? treatment toxicity efficacy preference impact on QoL Optimal treatment choice DFI cardiac damage
    47. 48. (7) Endocrine therapy is the preferred option for hormonal receptor-positive disease, unless there is concern or proof of endocrine resistance. Endocrine therapy of breast cancer is a very old targeted treatment…
    48. 49. <ul><li>For pre-menopausal women, tamoxifen combined with ovarian suppression/ablation is the first choice except for tamoxifen-resistant tumors. </li></ul>
    49. 50. The optimal first-line hormonal treatment for postmenopausal patients is an aromatase inhibitor ; however, tamoxifen remains a viable option. Optimal post-aromatase inhibitor treatment is uncertain, but tamoxifen , fulvestrant or a different aromatase inhibitor are possible options .
    50. 51. <ul><li>Maintenance of hormonal treatment after chemotherapy is not established, but is reasonable. </li></ul><ul><li>Concomitant chemo + endocrine therapy should be discouraged. </li></ul>
    51. 52. (8) Trastuzumab should be offered early to all HER-2-positive MBC patients, either combined with chemo or endocrine therapy or as a single agent .
    52. 53. Trastuzumab + chemotherapy Slamon, NEJM 2001 H0648g study probability of survival 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 25.4 20.3 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 trastuzumab + ChT ChT p=0.025 overall survival ( mths ) 5,1 mths
    53. 54. Trastuzumab + chemotherapy DFS Marty , J Clin Oncol. 2005 overall survival M77001 study Docetaxel + trastuzumab Docetaxel alone/crossover Docetaxel alone Estimated probability 1.0 0.8 0.6 0.4 0.2 0 0 3 6 9 12 15 18 21 24 27 30 33 36 Months 19.1 31.2 24.5 Estimated probability Months 6.1 11.7 Docetaxel + trastuzumab Docetaxel 0 0.2 0.4 0.6 0.8 1.0 0 3 6 9 12 15 18 21 24 27 30 33 36 p=0.0001 5,6 mths 12,1 mths
    54. 55. Trastuzumab + chemotherapy – subgroup analysis Marty, JCO 2005 M77001 study 0.1 1 10 100 Docetaxel better Trastuzumab + docetaxel better no difference Whole patient population Measurable disease and IHC 3+/FISH positive No previous anthracyclines Previous anthracyclines Age <50 years Age  50 years <24 months disease-free interval  24 months disease-free interval 1–2 metastatic organ sites >2 metastatic organ sites Visceral (lung or liver) metastases Non-visceral metastases ER and/or PgR positive ER and PgR negative/unknown ECOG performance status 0 ECOG performance status  1
    55. 56. time-to-progression Di Leo, ASCO 2007 Lapatinib – I line treatment p=0.007
    56. 57. overall survival Lapatinib – I line treatment Di Leo, ASCO 2007
    57. 58. Anti-HER2 therapy in combination with endocrine therapy is superior to endocrine therapy alone for HER-2 positive/ER positive disease .
    58. 59. ER – HER2 crosstalk Arpino , Endocr Rev 2008
    59. 60. 73 / 104 patients (70%) were crossed-over to trastuzumab on progression 0.4 PFS Mackey, SABCS 2006 Trastuzumab + hormonotherapy TAnDEM study months 0 5 10 15 20 25 30 35 40 45 50 55 60 overall survival p 0.325 Median OS 28.5 mths 23.9 mths 1.0 0.8 0.6 0.2 0.0 4.6 mths 2.4 mths 1.0 0.8 0.6 0.4 0.2 0 5 10 15 20 25 30 35 40 45 50 55 60 p 0.0016 Median PFS 4.8 mths 2.4 mths 0.0 HR 0.63 months
    60. 61. Trastuzumab + hormonotherapy Overall survival for patients on T + A vs A, excluding patients who crossed over to T Kaufman, JCO 2009
    61. 62. Lapatinib + letrozole Johnston , JCO 2009 HR-positive, HER2-positive patients PFS overall survival
    62. 63. Lapatinib + letrozole Johnston , JCO 2009 HER2(–) patients with <6 months since discontinuation of adjuvant tamoxifen
    63. 64. Patients progressing on an anti-HER-2 therapy combined with a cytotoxic agent should be offered a second combination of agents since it is important to keep blocking the HER-2 pathway in these tumours. Lapatinib combined with a cytotoxic agent is a viable option for patients progressing on trastuzumab .
    64. 65. GBG-26 Von Minckwitz, JCO 2009 Continuing trastuzumab beyond progression… capecitabine + trastuzumab (n=78) MBC HER2 + progressing on trastuzumab capecitabine (n=78) R
    65. 66. Continuing trastuzumab beyond progression… 54.0% 75.3% 27.0% 48.0% CR + PR p = 0.011 clinical benefit p = 0.0068 Von Minckwitz, JCO 2009
    66. 67. Von Minckwitz, JCO 2009 Continuing trastuzumab beyond progression… PFS 40 0 0.0 0.2 1.0 0.8 0.6 0.4 10 20 30 HR=0.69 p=0.015 8.2 5.6 capecitabine + trastuzumab (n=78) capecitabine (n=78) 20.4 40 0 0.0 0.2 1.0 0.8 0.6 0.4 10 20 30 HR=0.76 p=0.26 + + + + + + + + + + + + + 25.5 overall survival
    67. 68. Trastuzumab resistance <ul><li>p95 ErbB2 ~ 30% HER2 (+) breast cancers </li></ul>
    68. 69. Targets for anti-HER2 compounds trastuzumab lapatinib
    69. 70. Lapatinib – active in p95 ErbB2 (+) tumors Scaltriti , J NCI 2007
    70. 71. Scaltriti, Clin Cancer Research 2010 Lapatinib – active in p95 ErbB2 (+) tumors Lapatinib +capecitabine
    71. 72. EGF100151 Cameron, BCRT 2008 , Oncologist 2010 Lapatinib – post trastuzumab failure overall survival (weeks) time-to-progression (weeks)
    72. 73. PFS ( weeks ) Blackwell, JCO 2010 Combining targeted therapies…
    73. 74. Combining targeted therapies… Blackwell, JCO 2010 OS ( weeks )
    74. 75. (9) Both combination and sequential single agent monotherapy are reasonable first-line chemotherapy options. I n the absence of rapid clinical progression, life-threatening visceral metastases, or the need for rapid symptom and/or disease control sequential monotherapy i s the preferred choice in MBC.
    75. 76. (9) – contd. Patient- and disease-related factors should be used to choose between combination and sequential single-agent chemotherapy for MBC. Duration of each regimen and number of regimens should be tailored to each individual patient. Efficacy Toxicity
    76. 77. Median PFS/TTP (mths) Combination vs single agent? Pacilio 2006 9 months 0 2 4 6 8 10 Mu-oz 2006 Zielinski 2005 Albain 2004 O’Shaughnessy 2002 Jassem 2001 Mu-oz 2006 Seidman 2004 Chan 1999 Chan 1999 ET Gem + Vin Flu + Epi GT TX AT Vinorelbine Paclitaxel Doxorubicin Docetaxel
    77. 78. Combination vs single agent? m edian OS (mths) O’Shaughnessy 2002 Melemed 2007 Sledge 2003 Seidman 2004 Jones 2005 24 months 0 5 10 15 25 30 20 paclitaxel q3w paclitaxel q1w TX GT docetaxel
    78. 79. Combination vs single agent? <ul><li>E1193 </li></ul>Sledge, JCO 2003 doxorubicin vs paclitaxel vs doxo + paclitaxel time to treatment failure p=0.011 overall survival p=0.77
    79. 80. Combination vs single agent? randomized studies with planned cross-over Cardoso, JNCI 2009
    80. 81. Optimal therapy choice? <ul><li>monotherapy </li></ul><ul><ul><li>slow natural history </li></ul></ul><ul><ul><li>older age </li></ul></ul><ul><ul><li>poor PS </li></ul></ul><ul><ul><li>patient’s choice (continuing to work, etc.) </li></ul></ul><ul><li>combination chemotherapy </li></ul><ul><ul><li>rapid progression </li></ul></ul><ul><ul><li>need for rapid symptom control </li></ul></ul><ul><ul><li>visceral involvement </li></ul></ul><ul><ul><li>good PS </li></ul></ul>
    81. 82. <ul><li>in the past </li></ul>Chemotherapy – paradigm change now progression progression progression
    82. 83. Duration of chemotherapy Gennari, ESMO 2010
    83. 84. (10) There are few proven standards of care in MBC management. Therefore, inclusion of patients in well-designed, independent, prospective randomised trials must be a priority whenever available. Every proposed option must have a sound scientific rationale, preferably evidence-based.
    84. 85. (11) The medical community is aware of the problems raised by the cost of MBC treatment. Balanced decisions should be made in all instances, but the patient’s well-being, length and quality of life must always be the main decision factors.
    85. 86. Bewacizumab <ul><li>E2100 – progression free survival </li></ul>Miller, NEJM 200 7 0 20 40 60 80 100 Time (months) Progression-free survival estimate 0 10 20 30 40 6.7 13.3 HR=0.48; p<0.0001 99% increase in median PFS Median PFS (months) 15 10 5 0 Avastin + paclitaxel Paclitaxel Paclitaxel (n=354) Avastin + paclitaxel (n=368)
    86. 87. Bewacizumab Miller, NEJM 200 7 E2100 – overall survival no effect on survival!!! Months 1.0 0.8 0.6 0.4 0.2 0 HR=0.869 Log-rank test: p=0.1374 Paclitaxel + Avastin: median OS 26.5 months Paclitaxel: median OS 24.8 months OS estimate 0 6 12 18 24 30 36 42 48 54 60
    87. 88. Bewacizumab AVADO – progression free survival Mile s , ASCO 2008 BEV 7.5 mg/kg BEV 15 mg/kg Median 8.0 vs 8.7 mths HR 0 .79 (.63–.98) P = .0318 Mos PFS estimate 0 0.2 0.4 0.6 0.8 1.0 0 6 12 18 HR 0 .72 (.57–.90) P = .0036 Mos PFS estimate 0 0.2 0.4 0.6 0.8 1.0 0 6 12 18 Bev + Docetaxel (n = 248) Placebo + Docetaxel (n = 241) Median 8.0 vs 8.8 mths
    88. 89. (12) Formal (not just informal) quality of life assessments provide useful information and should be encouraged. If collected, such information should be integrated with that from clinic assessments to allow management decisions on initiating, changing, or stopping drug therapy.
    89. 90. Difficult issues triple-negative breast cancer
    90. 91. Inhomogenous disease „ triple negative” BC basal-like BC BRCA1 -related BC no single treatment is going to be effective high-grade ductal Ca metaplastic Ca apocrine Ca secretory Ca adenoid cystic Ca myoepithelial Ca medullary Ca high-grade lobular Ca neuroendocrine Ca
    91. 92. Choice of ChT <ul><li>anthracyclines? </li></ul><ul><ul><li>theory – ideal compounds </li></ul></ul><ul><ul><ul><li>frequent overexpression of Topo II  </li></ul></ul></ul><ul><ul><ul><li>BRCA mutation/dysfunction -> aberrant DNA repair </li></ul></ul></ul>
    92. 93. Anthracyclines? <ul><li>clinical data conflicting </li></ul>Di Leo, SABCS 2008, Cheang , ASCO 2009 NCIC-CTG MA5 A better CMF better HER2 amplified Triple negative Highly horm-sensitive Moderately horm-sensitive Metaanalysis British Columbia population-based
    93. 94. Choice of ChT <ul><li>taxanes? </li></ul><ul><ul><li>theory </li></ul></ul><ul><ul><ul><li>80% of TNBC are p53 mutant – potential benefit of taxanes? </li></ul></ul></ul>
    94. 95. Taxanes? <ul><li>clinical data conflicting </li></ul>Hayes, NEJM 2007, Ellis, Lancet 2009 CALGB 9344 all patients N+ patients TACT DFS
    95. 96. Choice of ChT <ul><li>platinum? </li></ul><ul><ul><li>theory </li></ul></ul><ul><ul><ul><li>platinum -> double strand DNA damage </li></ul></ul></ul><ul><ul><ul><li>TNBC - deficiency in BRCA associated DNA repair </li></ul></ul></ul>
    96. 97. Byrski, JCO 2010 Neoadjuvant treatment of 102 consecutive BRCA1 (+) breast cancer pts 83% 10 12 Cisplatin 8% 2 25 AT 21% 6 28 FAC 22% 5 23 AC 7% 1 14 CMF % pCR No of pCR No treated Regimen
    97. 98. Platinum in TNBC <ul><li>few prospective data exist </li></ul><ul><li>metronomic cyclophosphamide and methotrexate ± cisplatin in anthracycline and taxane pretreated TNBC pts </li></ul>Bhattacharyya, ECCO 2009 12 months 16 months OS 7 months 13 months PFS 30 % 62% RR no cisplatin cisplatin
    98. 99. <ul><li>synthetic lethality </li></ul>PARP-inhibitors Wild BRCA DNA damage BRCA PARP DNA repair DNA damage BRCA PARP DNA repair Inactive BRCA Wild BRCA DNA damage BRCA PARP DNA repair DNA damage BRCA PARP Inactive BRCA cell death
    99. 100. PARP-inhibitors O’Shaughnessy , NEJM 2011 „ triple negative„ BC 0–2 prior chemotherapy regimens for MBC
    100. 102. Thank you for your attention

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