TRIPLE NEGATIVE BREAST CANCER: an overview 10 th  ESO-ESMO Masterclass in Clinical Oncology 2-7 April 2011, Ermatingen (La...
Conflict of interest <ul><li>Involved in past 2 years in clinical trials & medical advisory boards financially supported b...
Find a drug before I have breasts
Framework <ul><li>Definition(s) </li></ul><ul><li>Natural History and Prognosis </li></ul><ul><li>Loco-Regional Treatment ...
Definition(s) <ul><li>Most of us learned in primary school that using a double negative is bad grammar.  </li></ul><ul><li...
Breast Cancer Biology Key Dates 1970s 1980s 1990s
Triple Negative Breast Cancer Definition <ul><li>Defined by the absence of « clinically meaningful » expression of targete...
Caveats 1: Endocrine sensitivity <ul><li>ER- & PgR+ tumors could be considered as non endocrine sensitive: in fact TNBC co...
Caveats 1: Endocrine sensitivity <ul><li>ER- & PgR+ tumours could be considered as non endocrine sensitive: in fact TNBC c...
Caveats 2: antiHER2 treatment sensitivity <ul><li>What is the threshold of positivity and by which method to consider a br...
 
Algorithm for HER2 and/or  HER2  testing  by IHC and/or FISH Wolff AC et al. JCO 2007
 
Caveats 2: antiHER2 treatment sensitivity <ul><li>What is the threshold of positivity and by which method to consider a br...
Caveats 3: molecular ≠ pathological  ≠ clinical definition « Basal-like » cancers  are associated with bad prognosis and  ...
Correspondence between Molecular Class and Clinicopathological Features of Breast Cancer Sotiriou V, Pusztai L. NEJM 2009
BRCA1 downregulation High   histological   grade Medullary   histological   type Basal-like   immunophenotype TN Hanneman ...
TNBC overlaps with BLBC a subgroup that expresses cytokeratins and other non-luminal (basal) genes.  Breast cancers occurr...
 
Clinical-pathological characteristics  of the current intrinsic subtypes of breast cancer Prat A, Perou CM. Molecular Onco...
Intrinsic subtype distribution within the triple-negative tumor category shown with and without Claudin-low tumors. Prat A...
Definition(s) – Conclusion 1 <ul><li>TNBC is different of BLBC, CLBC or BRCAness BC </li></ul><ul><li>Definition  of  nega...
Part of prognosis is always driven by pathology Basal-like and Triple Negative Breast Cancers High grade tumours Medullary...
Natural Histoty & Prognosis Prat A, Perou CM. Molecular Oncology 2011
Characteristics of triple-negative  versus other breast cancers Dent R et al. Clin Canc Res 2007
Tumor size by nodal status in the triple-negative and other groups Dent R et al. Clin Canc Res 2007 Method of breast cance...
Local Reccurence, Distant Reccurence and Death HRs in the TNBC group compared with the other group Dent R et al. Clin Canc...
Time is the most important issue <ul><li>&quot;We perceive, almost, only the past, the pure present being the elusive prog...
Local Reccurence, Distant Reccurence and Death HRs in the TNBC group compared with the other group Dent R et al. Clin Canc...
Rates of distant recurrences and breast-specific survival in TNBC and other breast cancers. RFS OS Dent R et al. Clin Canc...
Rates of distant recurrences following surgery in triple-negative and other breast cancers. Dent R et al. Clin Canc Res 2007
Sites of First Distant Recurrence in Cases of Metastatic TNBC as Compared with Non–TNBC <ul><li>TNBC and basal-like breast...
Natural Histoty & Prognosis- Conclusion 2 <ul><li>Some TNBC are of good prognosis (edenoid cystic, secretory…) </li></ul><...
Loco-Regional treatment strategies <ul><li>Do we have differences between tumour subtypes and risk of local relapse accord...
Local Reccurence, Distant Reccurence and Death HRs in the TNBC group compared with the other group Dent R et al. Clin Canc...
 
<ul><li>After mastectomy or conservative treatment luminal B, luminal-HER2, HER2-enriched, and basal subtypes were all ass...
There are limited single-arm prospective data for certain patient populations regarding the use of accelerated partial bre...
Natural Histoty & Prognosis Prat A, Perou CM. Molecular Oncology 2011
<ul><li>The neoadjuvant chemotherapy  </li></ul><ul><li>is as important for the oncologist  </li></ul><ul><li>as the white...
pCR and OS relationship Rastogi P et al. JCO 2008 NSABP B18 NSABP B27
Liedtke C et al. JCO 2008 pCR and OS relationship in TNBC
Loco-Regional treatment strategies – conclusion 3 <ul><li>It doesn ’ t seems that TN are at highest risk of local relapse ...
Systemic treatment <ul><li>What is the optimal adjuvant systemic treatment ? </li></ul><ul><li>What is the optimal metasta...
Adjuvant Systemic Treatments <ul><li>« Chemotherapy is currently the mainstay of systemic medical treatment, although pati...
Adjuvant Systemic Treatments:  can we move forward ? <ul><li>Importance of alkylating agents </li></ul><ul><li>Importance ...
Importance of Alkylating agents for TNBC MA5 Study - 710 patients - CMF vs CEF The interaction between basal status and tr...
 
 
 
TNBC platin compounds – refractory patients 1 Baselga et al. ESMO 2010;  2 O ’ Shaughnessy et al. ESMO 2010;  3 Carey et a...
Docetaxel RFS : meta-analyis Laporte S. et al, SABCS 2009
et al.
et al.
 
FINXX TRIAL Time to any recurrence:  Patients with triple-negative cancer (n=202) HR = 0.43 (p = 0.024) 95% CI 0.21 – 0.90...
Adjuvant Systemic Treatments – Conclusion 4 <ul><li>« Currently, there is no preferred standard form of chemotherapy for t...
Metastatic Systemic Treatments <ul><li>The place for clinical trials </li></ul><ul><li>The importance of patient selected ...
« New » chemotherapy agents <ul><li>Ixabepilone </li></ul><ul><li>Retrospective analysis from 5 phase II trials and a pros...
« Targeted » therapies  Gluz O et al. Ann Oncol 2009
 
Antiangiogenic drugs: Bevacizumab meta-analysis O’Shaugnessy J et al. ASCO 2010
Miles D et al. ESMO 2010
Structural and Functional characteristics of PARP1 Rouleau et al. Nat Rev Cancer 2010 10- to 500-fold increase in PARP1 ac...
The PARP family <ul><li>Sequence similarity with the PARP1 catalytric domain </li></ul><ul><ul><li>Genes encoding 16 struc...
Strategies to target PARP1 ionizing radiation  DNA-methylating agents NAD + Catalytic inhibition Nicotinamide
Strategies to target PARP1 ionizing radiation  DNA-methylating agents Catalytic inhibition Other PARPs Mono-ADP-ribosyl-tr...
Strategies to target PARP1 ionizing radiation  DNA-methylating agents PARP activity must be inhibited  by > 90% to detecta...
Clinical development approaches of PARP inhibitors Targeting cells genetically predisposed to die when PARP activity is lo...
Targeting cells genetically predisposed to die when PARP activity is lost
How to amplify  the target population ? <ul><li>Identifying tumour type with some of the properties of the BRCA1 or BRCA 2...
 
Perspectives Rouleau et al. Nat Rev Cancer 2010; 10: 293-301. Underhill C et al. Ann Oncol 2010; Epub of a print. > 30 ong...
Metastatic Systemic Treatments – Conclusion 6 <ul><li>The place for clinical trials +++ </li></ul><ul><li>The importance o...
P ersonalizing C ancer  C are
I Bergman The 7th Seal
The complexity of TNBC treatment strategies Thanks
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MCO 2011 - Slide 12 - J. Gligorov - Spotlight session - Triple negative breast cancer: An overview

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  • BV=bevacizumab, CI=confidence interval, ER=estrogen receptor, PR=progesterone receptor. Updated overall survival data with cutoff date of April 30, 2009 for AVADO and February 23, 2009 for RIBBON-1 was used for this analysis.
  • MCO 2011 - Slide 12 - J. Gligorov - Spotlight session - Triple negative breast cancer: An overview

    1. 1. TRIPLE NEGATIVE BREAST CANCER: an overview 10 th ESO-ESMO Masterclass in Clinical Oncology 2-7 April 2011, Ermatingen (Lake Constance), Switzerland Joseph Gligorov, MD APHP Tenon
    2. 2. Conflict of interest <ul><li>Involved in past 2 years in clinical trials & medical advisory boards financially supported by </li></ul><ul><ul><li>Astra-Zeneca </li></ul></ul><ul><ul><li>Bristol Myers Squib </li></ul></ul><ul><ul><li>Glaxo Smith Kline </li></ul></ul><ul><ul><li>Pfizer </li></ul></ul><ul><ul><li>Roche </li></ul></ul><ul><ul><li>Sanofi-Aventis </li></ul></ul>
    3. 3. Find a drug before I have breasts
    4. 4. Framework <ul><li>Definition(s) </li></ul><ul><li>Natural History and Prognosis </li></ul><ul><li>Loco-Regional Treatment Strategies </li></ul><ul><li>Systemic Treatment strategies </li></ul>
    5. 5. Definition(s) <ul><li>Most of us learned in primary school that using a double negative is bad grammar. </li></ul><ul><li>But a disease defined by three negatives, </li></ul><ul><li>triple-negative breast cancer (TNBC), has somehow sneaked into the oncology lexicon. </li></ul>Hede K. JNCI 2011
    6. 6. Breast Cancer Biology Key Dates 1970s 1980s 1990s
    7. 7. Triple Negative Breast Cancer Definition <ul><li>Defined by the absence of « clinically meaningful » expression of targeted therapy predictive factors: </li></ul><ul><ul><li>Endocrine treatments </li></ul></ul><ul><ul><ul><li>ER +/- PgR </li></ul></ul></ul><ul><ul><li>antiHER2 treatments </li></ul></ul><ul><ul><ul><li>HER2 overexpression or HER2 amplification </li></ul></ul></ul>TNBC is defined by ER & PgR & HER2 negative
    8. 8. Caveats 1: Endocrine sensitivity <ul><li>ER- & PgR+ tumors could be considered as non endocrine sensitive: in fact TNBC could be considered as double negative breast cancers: ER & HER2 negative </li></ul><ul><li>What is the threshold of positivity and by which method to consider a breast cancer as non endocrine sensitive? </li></ul>
    9. 9. Caveats 1: Endocrine sensitivity <ul><li>ER- & PgR+ tumours could be considered as non endocrine sensitive: in fact TNBC could be considered as double negative breast cancers: ER & HER2 negative </li></ul><ul><li>What is the threshold of positivity and by which method to consider a breast cancer as non endocrine sensitive? </li></ul>Endocrine sensitivity is defined by ER positivity It seems there is a « grey zone » of positivity between 0-10% IHC or 0-10 fmol/mg
    10. 10. Caveats 2: antiHER2 treatment sensitivity <ul><li>What is the threshold of positivity and by which method to consider a breast cancer as non candidate to antiHER2 therapies? </li></ul><ul><li>Are we sure the threshold is the same in different clinical situations (macro vs micro metastatic disease)? </li></ul>
    11. 12. Algorithm for HER2 and/or HER2 testing by IHC and/or FISH Wolff AC et al. JCO 2007
    12. 14. Caveats 2: antiHER2 treatment sensitivity <ul><li>What is the threshold of positivity and by which method to consider a breast cancer as non candidate to antiHER2 therapies? </li></ul><ul><li>Are we sure the threshold is the same in different clinical situations (macro vs micro metastatic disease)? </li></ul>antiHER2-treatments sensitivity is defined in guidelines by HER2 positivity (IHC and/or FISH) but some uncertainty exist concerning the threshold of positivity and tumour heterogeneity
    13. 15. Caveats 3: molecular ≠ pathological ≠ clinical definition « Basal-like » cancers are associated with bad prognosis and are frequently ER and HER2 negative: Triple negative ?
    14. 16. Correspondence between Molecular Class and Clinicopathological Features of Breast Cancer Sotiriou V, Pusztai L. NEJM 2009
    15. 17. BRCA1 downregulation High histological grade Medullary histological type Basal-like immunophenotype TN Hanneman et al EBCC6
    16. 18. TNBC overlaps with BLBC a subgroup that expresses cytokeratins and other non-luminal (basal) genes. Breast cancers occurring in patients with germline BRCA1 mutations are often TNBC & BLBC, bringing the hypothesis that BRCA1 defects or deficiency may be involved in sporadic TNBC and BLBC Carey L et al. Nat Rev Clin Oncol 2010
    17. 20. Clinical-pathological characteristics of the current intrinsic subtypes of breast cancer Prat A, Perou CM. Molecular Oncology 2011
    18. 21. Intrinsic subtype distribution within the triple-negative tumor category shown with and without Claudin-low tumors. Prat A, Perou CM. Molecular Oncology 2011
    19. 22. Definition(s) – Conclusion 1 <ul><li>TNBC is different of BLBC, CLBC or BRCAness BC </li></ul><ul><li>Definition of negative prediction to targeted treatments </li></ul><ul><ul><li>In clinical trials </li></ul></ul><ul><ul><ul><li>ER<1%, PgR<1%, (centrally determined ?) </li></ul></ul></ul><ul><ul><ul><li>HER2 negative status centrally determined </li></ul></ul></ul><ul><ul><li>In everyday practice </li></ul></ul><ul><ul><ul><li>ER<10%, PgR<10% </li></ul></ul></ul><ul><ul><ul><li>HER2 negative by IHC (0 or 1+) or ISH tech. Neg </li></ul></ul></ul>
    20. 23. Part of prognosis is always driven by pathology Basal-like and Triple Negative Breast Cancers High grade tumours Medullary breast cancer Metaplastic breast cancer Grade 3 – IDC-NST Low grade tumours Secretory carcinoma Adenoid cystic carcinoma Courtesy F Penault LLorca
    21. 24. Natural Histoty & Prognosis Prat A, Perou CM. Molecular Oncology 2011
    22. 25. Characteristics of triple-negative versus other breast cancers Dent R et al. Clin Canc Res 2007
    23. 26. Tumor size by nodal status in the triple-negative and other groups Dent R et al. Clin Canc Res 2007 Method of breast cancer detection in the triple-negative and other groups
    24. 27. Local Reccurence, Distant Reccurence and Death HRs in the TNBC group compared with the other group Dent R et al. Clin Canc Res 2007
    25. 28. Time is the most important issue <ul><li>&quot;We perceive, almost, only the past, the pure present being the elusive progress past gnawing the future.&quot; </li></ul><ul><ul><li>Henri Bergson, Matter and Memory </li></ul></ul>
    26. 29. Local Reccurence, Distant Reccurence and Death HRs in the TNBC group compared with the other group Dent R et al. Clin Canc Res 2007
    27. 30. Rates of distant recurrences and breast-specific survival in TNBC and other breast cancers. RFS OS Dent R et al. Clin Canc Res 2007
    28. 31. Rates of distant recurrences following surgery in triple-negative and other breast cancers. Dent R et al. Clin Canc Res 2007
    29. 32. Sites of First Distant Recurrence in Cases of Metastatic TNBC as Compared with Non–TNBC <ul><li>TNBC and basal-like breast cancers are more likely than other types of breast cancer to metastasize to viscera </li></ul><ul><li>Particularly to the lungs and brain </li></ul><ul><li>TNBC and basal-like breast cancers are less likely to metastasize to bone </li></ul>Foulkes WD et al. NEJM 2010
    30. 33. Natural Histoty & Prognosis- Conclusion 2 <ul><li>Some TNBC are of good prognosis (edenoid cystic, secretory…) </li></ul><ul><li>Often present as interval cancers </li></ul><ul><li>Weak relationship between pT & pN </li></ul><ul><li>Rapid rise in risk of recurrence following diagnosis </li></ul><ul><li>Peak risk of recurrence at 1-3 y </li></ul><ul><li>Local recurrence not predictive of distal recurrence </li></ul><ul><li>More frequent sites of distant mets (brain, lung) </li></ul><ul><li>Distal recurrence rarely preceded by local recurrence </li></ul><ul><li>Increased mortality rate first 5 y </li></ul><ul><li>Majority of deaths occur in first 5 y </li></ul><ul><li>Rapid progression from distant recurrence to death </li></ul>
    31. 34. Loco-Regional treatment strategies <ul><li>Do we have differences between tumour subtypes and risk of local relapse according to the loco-regional treatment ? </li></ul><ul><li>Do we have arguments for modifying our local treatments in TNBC ? </li></ul><ul><ul><li>Type of surgery </li></ul></ul><ul><ul><li>Type of radiotherapy </li></ul></ul><ul><li>Do we have arguments to modify the sequence of the loco-regional treatment / systemic treatments ? </li></ul>
    32. 35. Local Reccurence, Distant Reccurence and Death HRs in the TNBC group compared with the other group Dent R et al. Clin Canc Res 2007
    33. 37. <ul><li>After mastectomy or conservative treatment luminal B, luminal-HER2, HER2-enriched, and basal subtypes were all associated with an increased risk of local and regional relapse on multivariable analysis </li></ul><ul><li>Luminal A tumors are associated with a low risk of local or regional recurrence </li></ul>
    34. 38. There are limited single-arm prospective data for certain patient populations regarding the use of accelerated partial breast irradiation, including those with negative ES receptor satus.
    35. 39. Natural Histoty & Prognosis Prat A, Perou CM. Molecular Oncology 2011
    36. 40. <ul><li>The neoadjuvant chemotherapy </li></ul><ul><li>is as important for the oncologist </li></ul><ul><li>as the white stick for a blind person </li></ul>www.zebracorn.com
    37. 41. pCR and OS relationship Rastogi P et al. JCO 2008 NSABP B18 NSABP B27
    38. 42. Liedtke C et al. JCO 2008 pCR and OS relationship in TNBC
    39. 43. Loco-Regional treatment strategies – conclusion 3 <ul><li>It doesn ’ t seems that TN are at highest risk of local relapse comparing to other non-luminal A subtypes </li></ul><ul><li>We do not have any biological arguments actually to change our local treatment strategies </li></ul><ul><ul><li>Type of surgery </li></ul></ul><ul><ul><li>Type of radiotherapy </li></ul></ul><ul><li>Maybe the neoadjuvant approach is clearly appropriate to investigate systemic treatment strategies in TNBC </li></ul>
    40. 44. Systemic treatment <ul><li>What is the optimal adjuvant systemic treatment ? </li></ul><ul><li>What is the optimal metastatic systemic treatment ? </li></ul><ul><li>Could we expect important progresses ? </li></ul>
    41. 45. Adjuvant Systemic Treatments <ul><li>« Chemotherapy is currently the mainstay of systemic medical treatment, although patients with TNBC have a worse outcome after chemotherapy than patients with breast cancers of other subtypes » </li></ul><ul><li>« Currently, there is no preferred standard form of chemotherapy for triple-negative breast cancer, and treatment should be selected as it is for other cancer subtypes » </li></ul>Foulkes WD et al. NEJM 2010
    42. 46. Adjuvant Systemic Treatments: can we move forward ? <ul><li>Importance of alkylating agents </li></ul><ul><li>Importance of anthracyclines </li></ul><ul><li>Importance of taxanes </li></ul><ul><li>Importance of dose-density </li></ul><ul><li>Importance of capecitabine </li></ul>
    43. 47. Importance of Alkylating agents for TNBC MA5 Study - 710 patients - CMF vs CEF The interaction between basal status and treatment is borderline significant (p=0.06) Test of main hypothesis: comparison of overall survival in core basal patients versus all other subtypes in MA5, stratified by treatment arm Evaluation immunohistochimique de ER, PR, HER2, Ki67, CK5/6, EGFR Cheang M et al. ASCO 2009 Biological subtype and treatments N 5-Year OS (95% CI) P-value Hazard ratio (95% CI) Log-rank Wilcoxon CEF Core basal 35 51% (35-68) 0.02 0.002 1.84 (1.09-3.11) All others 209 80% (74-85) CMF Core basal 35 71% (56-86) 0.72 0.74 0.90 (0.50-1.60) All others 232 71% (64-76)
    44. 51. TNBC platin compounds – refractory patients 1 Baselga et al. ESMO 2010; 2 O ’ Shaughnessy et al. ESMO 2010; 3 Carey et al. ASCO 2008 Study Platin arm Doses N First line ORR (%) PFS BALI-1 1 Cisplatin 75 mg/m 2 q3w 58 73% 6 (10.3%) 1.5 months BSI-201 2 Carbo - Gem AUC 2 d1, 8 q3w 1000 mg/m 2 d1, 8 62 60% 20 (32,2%) 3.6 months TBCRC-001 3 Carbo – Cetuximab AUC 2 d1, 8, 15 q4w 71 46% 13 (18%) 2.0 months
    45. 52. Docetaxel RFS : meta-analyis Laporte S. et al, SABCS 2009
    46. 53. et al.
    47. 54. et al.
    48. 56. FINXX TRIAL Time to any recurrence: Patients with triple-negative cancer (n=202) HR = 0.43 (p = 0.024) 95% CI 0.21 – 0.90 HR: 0.43, 95% CI 0.21–0.90 P = 0.024 TX + CEX, n=93 T + CEF, n=109 Courtesy H Joensuu
    49. 57. Adjuvant Systemic Treatments – Conclusion 4 <ul><li>« Currently, there is no preferred standard form of chemotherapy for triple-negative breast cancer, and treatment should be selected as it is for other cancer subtypes » </li></ul><ul><li>However, we have to be careful because TNBC are possibly in general more chemo sensitive so: </li></ul><ul><ul><ul><li>Do not forget alkylating agent (cyclophosphamide) </li></ul></ul></ul><ul><ul><ul><li>Respect Dose-Intensity </li></ul></ul></ul><ul><ul><ul><li>Certainly integrating taxanes </li></ul></ul></ul><ul><ul><ul><li>No arguments to avoid anthracyclines (neoadjuvant experience) </li></ul></ul></ul>Foulkes WD et al. NEJM 2010
    50. 58. Metastatic Systemic Treatments <ul><li>The place for clinical trials </li></ul><ul><li>The importance of patient selected populations </li></ul><ul><li>The differences according to drug access </li></ul>
    51. 59. « New » chemotherapy agents <ul><li>Ixabepilone </li></ul><ul><li>Retrospective analysis from 5 phase II trials and a prospective pooled analysis from 2 phase III trials </li></ul><ul><li>2,261 patients evaluated, 556 (24.5%) had triple-negative tumors. </li></ul><ul><li>NA 26%pCR (vs. 15% in the non-TNBC) </li></ul><ul><li>In TN MBC ORR: 6 to 55%, </li></ul><ul><li>The median PFS was significantly longer for triple-negative patients treated with ixabepilone plus capecitabine (4.2 months) compared with treatment with capecitabine alone (1.7 months). </li></ul>Perez E et al. BCRT 2010
    52. 60. « Targeted » therapies Gluz O et al. Ann Oncol 2009
    53. 62. Antiangiogenic drugs: Bevacizumab meta-analysis O’Shaugnessy J et al. ASCO 2010
    54. 63. Miles D et al. ESMO 2010
    55. 64. Structural and Functional characteristics of PARP1 Rouleau et al. Nat Rev Cancer 2010 10- to 500-fold increase in PARP1 activity PARP1 is active in a homodimeric form The dense negative charge of pADPr succeeds has the loss of affinity of PARP1 for DNA and allowes the recruitement of repair proteins
    56. 65. The PARP family <ul><li>Sequence similarity with the PARP1 catalytric domain </li></ul><ul><ul><li>Genes encoding 16 structurally related proteins (members of the so-called PARP family) have been identified </li></ul></ul><ul><li>Can transfer the first ADP-ribose moiety from NAD + to an acceptor protein and can sequentially add multiple ADP-ribose units to form pADPr chains </li></ul><ul><ul><li>Only six of these proteins may actually be considered as poly(ADP-ribose) polymerases and are subdivided in three groups </li></ul></ul><ul><li>PARP1 , PARP2 and PARP3 </li></ul><ul><li>PARP4 (vault PARP) </li></ul><ul><li>TNKS1 and TNKS2 (Tankyrases) </li></ul>
    57. 66. Strategies to target PARP1 ionizing radiation DNA-methylating agents NAD + Catalytic inhibition Nicotinamide
    58. 67. Strategies to target PARP1 ionizing radiation DNA-methylating agents Catalytic inhibition Other PARPs Mono-ADP-ribosyl-transferase Sirtuins … NAD + Nicotinamide
    59. 68. Strategies to target PARP1 ionizing radiation DNA-methylating agents PARP activity must be inhibited by > 90% to detectably impair DNA repair
    60. 69. Clinical development approaches of PARP inhibitors Targeting cells genetically predisposed to die when PARP activity is lost Combining PARP inhibitors with DNA-damaging agents
    61. 70. Targeting cells genetically predisposed to die when PARP activity is lost
    62. 71. How to amplify the target population ? <ul><li>Identifying tumour type with some of the properties of the BRCA1 or BRCA 2 deficient cells: </li></ul><ul><ul><li>The triple negative approach </li></ul></ul><ul><ul><li>PTEN-deficient cells (PTEN is important for the expression of the repair protein RAD51) </li></ul></ul><ul><ul><li>Other tumour types </li></ul></ul><ul><li>Pairing PARP inhibitors with DNA-damaging agents: methylating agents, topoisomerase I poisons, alkylating agents, ionizing radiation agents </li></ul>
    63. 73. Perspectives Rouleau et al. Nat Rev Cancer 2010; 10: 293-301. Underhill C et al. Ann Oncol 2010; Epub of a print. > 30 ongoing clinical trials with PARPi & DNA-damaging agents > 10 ongoing clinical trials with PARPi alone > 10 ongoing clinical trials with PARPi alone > 10 ongoing clinical trials with PARPi & DNA-damaging agents Unselected Population BRCA mutant BRCAness
    64. 74. Metastatic Systemic Treatments – Conclusion 6 <ul><li>The place for clinical trials +++ </li></ul><ul><li>The importance of patient selected populations +++ </li></ul><ul><li>The differences according to drug access +++ </li></ul><ul><li>New promising agents </li></ul><ul><ul><li>Certainly important to consider the population “ chemodependant ” </li></ul></ul><ul><ul><li>Better define the place for antiangiogenic drugs </li></ul></ul><ul><ul><li>Certainly integrate in the very next futur PARP1 inhibitors </li></ul></ul>
    65. 75. P ersonalizing C ancer C are
    66. 76. I Bergman The 7th Seal
    67. 77. The complexity of TNBC treatment strategies Thanks

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