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.
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
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
Caveats 3: molecular ≠ pathological ≠ clinical definition « Basal-like » cancers are associated with bad prognosis and are frequently ER and HER2 negative: Triple negative ?
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 et al EBCC6
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
Definition of negative prediction to targeted treatments
In clinical trials
ER<1%, PgR<1%, (centrally determined ?)
HER2 negative status centrally determined
In everyday practice
HER2 negative by IHC (0 or 1+) or ISH tech. Neg
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
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 cancer detection in the triple-negative and other groups
Local Reccurence, Distant Reccurence and Death HRs in the TNBC group compared with the other group Dent R et al. Clin Canc Res 2007
« 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
Adjuvant Systemic Treatments: can we move forward ?
Importance of alkylating agents
Importance of anthracyclines
Importance of taxanes
Importance of dose-density
Importance of capecitabine
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)
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
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