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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.
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    • 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. Conflict of interest
      • Involved in past 2 years in clinical trials & medical advisory boards financially supported by
        • Astra-Zeneca
        • Bristol Myers Squib
        • Glaxo Smith Kline
        • Pfizer
        • Roche
        • Sanofi-Aventis
    • 3. Find a drug before I have breasts
    • 4. Framework
      • Definition(s)
      • Natural History and Prognosis
      • Loco-Regional Treatment Strategies
      • Systemic Treatment strategies
    • 5. Definition(s)
      • Most of us learned in primary school that using a double negative is bad grammar.
      • But a disease defined by three negatives,
      • triple-negative breast cancer (TNBC), has somehow sneaked into the oncology lexicon.
      Hede K. JNCI 2011
    • 6. Breast Cancer Biology Key Dates 1970s 1980s 1990s
    • 7. Triple Negative Breast Cancer Definition
      • Defined by the absence of « clinically meaningful » expression of targeted therapy predictive factors:
        • Endocrine treatments
          • ER +/- PgR
        • antiHER2 treatments
          • HER2 overexpression or HER2 amplification
      TNBC is defined by ER & PgR & HER2 negative
    • 8. Caveats 1: Endocrine sensitivity
      • ER- & PgR+ tumors could be considered as non endocrine sensitive: in fact TNBC could be considered as double negative breast cancers: ER & HER2 negative
      • What is the threshold of positivity and by which method to consider a breast cancer as non endocrine sensitive?
    • 9. Caveats 1: Endocrine sensitivity
      • ER- & PgR+ tumours could be considered as non endocrine sensitive: in fact TNBC could be considered as double negative breast cancers: ER & HER2 negative
      • What is the threshold of positivity and by which method to consider a breast cancer as non endocrine sensitive?
      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. Caveats 2: antiHER2 treatment sensitivity
      • What is the threshold of positivity and by which method to consider a breast cancer as non candidate to antiHER2 therapies?
      • Are we sure the threshold is the same in different clinical situations (macro vs micro metastatic disease)?
    • 11.  
    • 12. Algorithm for HER2 and/or HER2 testing by IHC and/or FISH Wolff AC et al. JCO 2007
    • 13.  
    • 14. Caveats 2: antiHER2 treatment sensitivity
      • What is the threshold of positivity and by which method to consider a breast cancer as non candidate to antiHER2 therapies?
      • Are we sure the threshold is the same in different clinical situations (macro vs micro metastatic disease)?
      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
    • 15. Caveats 3: molecular ≠ pathological ≠ clinical definition « Basal-like » cancers are associated with bad prognosis and are frequently ER and HER2 negative: Triple negative ?
    • 16. Correspondence between Molecular Class and Clinicopathological Features of Breast Cancer Sotiriou V, Pusztai L. NEJM 2009
    • 17. BRCA1 downregulation High histological grade Medullary histological type Basal-like immunophenotype TN Hanneman et al EBCC6
    • 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
    • 19.  
    • 20. Clinical-pathological characteristics of the current intrinsic subtypes of breast cancer Prat A, Perou CM. Molecular Oncology 2011
    • 21. Intrinsic subtype distribution within the triple-negative tumor category shown with and without Claudin-low tumors. Prat A, Perou CM. Molecular Oncology 2011
    • 22. Definition(s) – Conclusion 1
      • TNBC is different of BLBC, CLBC or BRCAness BC
      • Definition of negative prediction to targeted treatments
        • In clinical trials
          • ER<1%, PgR<1%, (centrally determined ?)
          • HER2 negative status centrally determined
        • In everyday practice
          • ER<10%, PgR<10%
          • HER2 negative by IHC (0 or 1+) or ISH tech. Neg
    • 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
    • 24. Natural Histoty & Prognosis Prat A, Perou CM. Molecular Oncology 2011
    • 25. Characteristics of triple-negative versus other breast cancers Dent R et al. Clin Canc Res 2007
    • 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
    • 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
    • 28. Time is the most important issue
      • &quot;We perceive, almost, only the past, the pure present being the elusive progress past gnawing the future.&quot;
        • Henri Bergson, Matter and Memory
    • 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
    • 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
    • 31. Rates of distant recurrences following surgery in triple-negative and other breast cancers. Dent R et al. Clin Canc Res 2007
    • 32. Sites of First Distant Recurrence in Cases of Metastatic TNBC as Compared with Non–TNBC
      • TNBC and basal-like breast cancers are more likely than other types of breast cancer to metastasize to viscera
      • Particularly to the lungs and brain
      • TNBC and basal-like breast cancers are less likely to metastasize to bone
      Foulkes WD et al. NEJM 2010
    • 33. Natural Histoty & Prognosis- Conclusion 2
      • Some TNBC are of good prognosis (edenoid cystic, secretory…)
      • Often present as interval cancers
      • Weak relationship between pT & pN
      • Rapid rise in risk of recurrence following diagnosis
      • Peak risk of recurrence at 1-3 y
      • Local recurrence not predictive of distal recurrence
      • More frequent sites of distant mets (brain, lung)
      • Distal recurrence rarely preceded by local recurrence
      • Increased mortality rate first 5 y
      • Majority of deaths occur in first 5 y
      • Rapid progression from distant recurrence to death
    • 34. Loco-Regional treatment strategies
      • Do we have differences between tumour subtypes and risk of local relapse according to the loco-regional treatment ?
      • Do we have arguments for modifying our local treatments in TNBC ?
        • Type of surgery
        • Type of radiotherapy
      • Do we have arguments to modify the sequence of the loco-regional treatment / systemic treatments ?
    • 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
    • 36.  
    • 37.
      • 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
      • Luminal A tumors are associated with a low risk of local or regional recurrence
    • 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.
    • 39. Natural Histoty & Prognosis Prat A, Perou CM. Molecular Oncology 2011
    • 40.
      • The neoadjuvant chemotherapy
      • is as important for the oncologist
      • as the white stick for a blind person
      www.zebracorn.com
    • 41. pCR and OS relationship Rastogi P et al. JCO 2008 NSABP B18 NSABP B27
    • 42. Liedtke C et al. JCO 2008 pCR and OS relationship in TNBC
    • 43. Loco-Regional treatment strategies – conclusion 3
      • It doesn ’ t seems that TN are at highest risk of local relapse comparing to other non-luminal A subtypes
      • We do not have any biological arguments actually to change our local treatment strategies
        • Type of surgery
        • Type of radiotherapy
      • Maybe the neoadjuvant approach is clearly appropriate to investigate systemic treatment strategies in TNBC
    • 44. Systemic treatment
      • What is the optimal adjuvant systemic treatment ?
      • What is the optimal metastatic systemic treatment ?
      • Could we expect important progresses ?
    • 45. Adjuvant Systemic Treatments
      • « 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 »
      • « 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 »
      Foulkes WD et al. NEJM 2010
    • 46. Adjuvant Systemic Treatments: can we move forward ?
      • Importance of alkylating agents
      • Importance of anthracyclines
      • Importance of taxanes
      • Importance of dose-density
      • Importance of capecitabine
    • 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)
    • 48.  
    • 49.  
    • 50.  
    • 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
    • 52. Docetaxel RFS : meta-analyis Laporte S. et al, SABCS 2009
    • 53. et al.
    • 54. et al.
    • 55.  
    • 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
    • 57. Adjuvant Systemic Treatments – Conclusion 4
      • « 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 »
      • However, we have to be careful because TNBC are possibly in general more chemo sensitive so:
          • Do not forget alkylating agent (cyclophosphamide)
          • Respect Dose-Intensity
          • Certainly integrating taxanes
          • No arguments to avoid anthracyclines (neoadjuvant experience)
      Foulkes WD et al. NEJM 2010
    • 58. Metastatic Systemic Treatments
      • The place for clinical trials
      • The importance of patient selected populations
      • The differences according to drug access
    • 59. « New » chemotherapy agents
      • Ixabepilone
      • Retrospective analysis from 5 phase II trials and a prospective pooled analysis from 2 phase III trials
      • 2,261 patients evaluated, 556 (24.5%) had triple-negative tumors.
      • NA 26%pCR (vs. 15% in the non-TNBC)
      • In TN MBC ORR: 6 to 55%,
      • 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).
      Perez E et al. BCRT 2010
    • 60. « Targeted » therapies Gluz O et al. Ann Oncol 2009
    • 61.  
    • 62. Antiangiogenic drugs: Bevacizumab meta-analysis O’Shaugnessy J et al. ASCO 2010
    • 63. Miles D et al. ESMO 2010
    • 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
    • 65. The PARP family
      • Sequence similarity with the PARP1 catalytric domain
        • Genes encoding 16 structurally related proteins (members of the so-called PARP family) have been identified
      • 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
        • Only six of these proteins may actually be considered as poly(ADP-ribose) polymerases and are subdivided in three groups
      • PARP1 , PARP2 and PARP3
      • PARP4 (vault PARP)
      • TNKS1 and TNKS2 (Tankyrases)
    • 66. Strategies to target PARP1 ionizing radiation DNA-methylating agents NAD + Catalytic inhibition Nicotinamide
    • 67. Strategies to target PARP1 ionizing radiation DNA-methylating agents Catalytic inhibition Other PARPs Mono-ADP-ribosyl-transferase Sirtuins … NAD + Nicotinamide
    • 68. Strategies to target PARP1 ionizing radiation DNA-methylating agents PARP activity must be inhibited by > 90% to detectably impair DNA repair
    • 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
    • 70. Targeting cells genetically predisposed to die when PARP activity is lost
    • 71. How to amplify the target population ?
      • Identifying tumour type with some of the properties of the BRCA1 or BRCA 2 deficient cells:
        • The triple negative approach
        • PTEN-deficient cells (PTEN is important for the expression of the repair protein RAD51)
        • Other tumour types
      • Pairing PARP inhibitors with DNA-damaging agents: methylating agents, topoisomerase I poisons, alkylating agents, ionizing radiation agents
    • 72.  
    • 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
    • 74. Metastatic Systemic Treatments – Conclusion 6
      • The place for clinical trials +++
      • The importance of patient selected populations +++
      • The differences according to drug access +++
      • New promising agents
        • Certainly important to consider the population “ chemodependant ”
        • Better define the place for antiangiogenic drugs
        • Certainly integrate in the very next futur PARP1 inhibitors
    • 75. P ersonalizing C ancer C are
    • 76. I Bergman The 7th Seal
    • 77. The complexity of TNBC treatment strategies Thanks