BIOMARKERS Roberto Bordonaro Struttura Complessa di Oncologia Medica
BIOMARKERS. Roberto Bordonaro Struttura Complessa di Oncologia Medica ARNAS Garibaldi Catania
BIOMARKERS. - The management of breast cancer, both in early and in advanced stages, had become a “receptor-driven therapy”. - Main breast cancer determinants have both prognostic and predictive role, such as ER, Pg. R and Her 2. - They also reflect the moment when the cell develops the tumor phenotype.
image by Katie Vicari, from Prat and Perou, Nature Medicine, Aug; 15(8): 842 -4 (2009)
Her 2+ve tumours Her 2+ve / ER and/or Pg. R+ve image by Katie Vicari, from Prat and Perou, Nature Medicine, Aug; 15(8): 842 -4 (2009)
Her 2+ve tumours Her 2+ve / ER and/or Pg. R+ve image by Katie Vicari, from Prat and Perou, Nature Medicine, Aug; 15(8): 842 -4 (2009)
BIOMARKERS. • Triple-negative breast cancer are a heterogenous subgroup of tumours. • The 75 per cent of them shown a “Basal-like signature” (more than a half express TP 53 mutations, some are BRCA 1 -mut carriers). • They have high proliferative rate and a poor prognosis (in terms of poor relapse-free and/or overall survival).
Claudin-low Subtype HER 2 1. 5 -10% of all tumors 2. typically TNBC 3. low expression of cell-cell junction proteins 4. lymphocyte infiltrates 5. stem cell + EMT features Basal Luminal Proliferation Claudin 3 Claudin 4 Claudin 7 E-Cadherin
Claudin-low Subtype HER 2 1. 5 -10% of all tumors 2. typically TNBC 3. low expression of cell-cell junction proteins 4. lymphocyte infiltrates 5. stem cell + EMT features Basal Luminal Proliferation Claudin 3 Claudin 4 Claudin 7 E-Cadherin
Phenotypic and Molecular Characterization of the Claudin-low Intrinsic Subtype of Breast Cancer, Prat et al. , Breast Cancer Res. 2010 Sep 2; 12(5): R 68. (PMID: 20813035)
● ● HER 2 CRYAB ID 4 EGFR/HER 1 c-KIT Keratin 5 Keratin 17 P-Cadherin Luminal Proliferation Basal-like phenotype (75% of TNBC cancers; 10 -20% of BC); >50% TP 53 -mutated; high proliferative rate (RB loss) DNA-recombination defects related to BRCA 1 -mutations.
● ● HER 2 CRYAB ID 4 EGFR/HER 1 c-KIT Keratin 5 Keratin 17 P-Cadherin Luminal Proliferation Basal-like phenotype (75% of TNBC cancers; 10 -20% of BC); >50% TP 53 -mutated; high proliferative rate (RB loss) DNA-recombination defects related to BRCA 1 -mutations.
Deconstructing the Molecular Portraits of Breast Cancer, Prat and Perou, Molecular Oncology, Nov 24, 2010 (PMID: 21147047)
BRCA 1 - Associated Breast Cancer • One defective gene copy carried in a germ cell • 5 -10% of breast cancers • 50 -90% lifetime risk of disease • Shared characteristics with sporadic basal-like breast cancer: “BRCA-ness” • • • “BRCAness” High grade ER- and HER 2 -negative C-myc amplified Medullary Pushing margins DCIS less common Lymphocytic infiltrate TP 53 mutations Basal phenotype EGFR expression X-chromosome inactivation pattern • Sensitivity to DNA damage
BRCA 1 Is Key to Repairing DNA Damage Several DNA damage response pathways exist: • Homologous recombination (HR) – DEPENDS ON BRCA 1 • Base excision repair (BER) – DEPENDS ON PARP • Nucleotide excision repair (NER) • Mismatch repair (MMR)
Platinum-sensitivity of BRCA 1 mut – TNBCs Trial Byrski Silver Characteristics Regimen n° p. RC BRCA 1+mut carriers Not-platinum-based 90 14 (16%) BRCA 1+mut carriers CDDP 75 mg/m 2 x 4 12 10 (83%) sporadics TNBCs (not BRCA 1+mut carriers) CDDP 75 mg/m 2 x 4 26 4 (15%) 2 2 (100%) 51 8 (16%) BRCA 1 mut carriers Ryan • • sporadics TNBCs (not BRCA 1+mut carriers) “ “ CDDP 75 mg/m 2 x 4 + bevacizumab 15 mg/kg q 3 wk x 3 Neo-adjuvant setting: – Retrospective trials suggest platinum-based regimens activity; – Data from prospective trials on TNBCs are controversial; Metastatics TNBCs: – control arm in BALI-1 study with DDP alone – 10% RR Byrski, JCO 2009; Silver JCO 2009: Baselga ESMO 2010; Isakoff SABCS 2010
Good platinum response (p =) Young age . 001 low BRCA 1 m. RNA expression . 03 BRCA 1 promoter methylation . 04 p 53 mutation . 01 gene expression profile of E 2 F 3 activation . 03 Interesting biological analysis; small series (28), only two BRCA 1 mutation carriers enrolled.
Biomarkers. • Are there any biological characteristic expressed by triple-negative tumours that may influence therapeutic choice?
A compact VEGF signature associated with distant metastases and poor outcomes, Hu et al. BMC Medicine 2009, doi: 10. 1186/1741 -7015 -7 -9 FOS/JUN Fibroblast CXCL 12 Immune Cell 13 -gene VEGFsignature
A compact VEGF signature associated with distant metastases and poor outcomes, Hu et al. BMC Medicine 2009, doi: 10. 1186/1741 -7015 -7 -9 FOS/JUN Fibroblast CXCL 12 Immune Cell 13 -gene VEGFsignature
Expression Hypoxia-related Features and Basal-like Tumors VEGF 13 -gene VEGF-signature • Antiangiogenic approaches work in TNBC at least as well as other subtype, possibly more. Hu, BMC Medicine 2009
A compact VEGF signature associated with distant metastases and poor outcomes, Hu et al. BMC Medicine 2009, doi: 10. 1186/1741 -7015 -7 -9
Identification of a clinically relevant gene signature in triple negative and basal like breast cancer. Rody et al. SABCS 2010 Oral Presentation. slide courtesy of Lajos Pusztai (MDACC)
679 consecutive Bc patients; among them, 87 (13%) where ER, Pg. R and Her 2 -ve. TN patients had significantly higher VEGF activiity: m. Value = 8. 2 pg/μg (versus 2. 7 pg/μg in non-TN ones; p <. 001) 62% of TN-patients had a VEGF acitivity above the median value, respect to the 47% of ER and/or Pg. R and/or Her 2+ve ones. (p = 0. 036). TN status seems do not correlate with other clinical prognostic factors such as Tumour size (p = 0. 07), nodal status (p =0. 1), histological grade (p = 0. 17) type of relapse (p = 0. 82), age (p = 0. 18). Her 2 overexpression was associated with high levels of VEGF (p <. 001).
RFS d. DFS OS BCCS Linderholm, Ann Oncol 2009
Outcome parameters Univariate Multivariate RFS H. r. significance (p) TNBC 1. 8 0. 0023 1. 7 0. 078 VEGF 1. 6 0. 0057 1. 3 0. 1663 TNBC 1. 6 0. 087 1. 3 0. 4099 VEGF 1. 7 0. 0166 1. 4 0. 2136 TNBC 1. 8 0. 0048 1. 5 0. 1672 VEGF 1. 6 0. 0021 1. 3 0. 1353 TNBC 2. 2 0. 0039 1. 6 0. 2621 VEGF 2. 0 0. 0044 1. 5 0. 0921 d. DFS OS BCSS Linderholm, Ann Oncol 2009
Biomarkers. • But, which chemoterapeutic agents shown activity and/or efficacy when administered to triple-negative breast cancer?
Pathologic Response to Anthracycline/Taxane by Subtype 369 patients from 3 neoadjuvant datasets Modified PAM 50 Overall p. CR rate = 22% (82/369) Residual dz p. CR 47 (58%) 34 (42%) 29 (67%) 14 (33%) 31 (63%) 18 (37%) Lum. A 110 (98%) 2 (2%) Lum. B 56 (85%) 10 (15%) Normal-like 13 (76%) 4 (24%) Classification Basal-like Claudin-low HER 2 -enriched Courtesy C. Perou Majority of TNBC
Chemotherapy Advances Benefit Triple Negative ER Positive HER 2 NEG paclitaxel No paclitaxel • Anthracycline added to CMF No paclitaxel HER 2 POS • Docetaxel – Same findings (ECOG/Geicam) No paclitaxel (CALGB 9344: AC + Paclitaxel) Hayes, NEJM 2008; Perez, BCRT 2010; Di Leo, SABCS 2008 No paclitaxel
Anthracycline versus Non-Anthracycline MA. 5 Revisited CEF Biologic # 5 Year Subtype OS Luminal A 62 93% Luminal NOS 36 94% Luminal B 67 71% Luminal B 21 71% He. R 2+/ER 20 55% Basal by IHC 35 51% TNBC Non-Basal 9 65% # CMF 5 Year 71 26 65 27 23 35 20 p OS 90% 85% 71% 44% <0. 001 30% 71% <0. 0001 63% Intriguing, although retrospective and small Cheang M et al, ASCO 2009
Responsiveness to Conventional Chemotherapy Basal-like / triple negative: Often responsive If p. CR achieved = good outcome! Nonresponse = poor outcome
Predicting Markers of Clinical Benefit • VEGF genotypes associated with improved OS in E 2100. • Higher levels of circulating endothelial cells at baseline have consistently correlated with prolonged clinical benefit and in one study improved TTP Dahlberg SE, et al. J Clin Oncol. 2010; 28: 949 -954
Biomarkers. • AVF 2119: 462 patients with MBC randomized to receive Capecitabine alone or capecitabine plus Bevacizumab. • Among them, for 223 patients tissue samples were collected and tested with: • a) in situ hybridization (VEGF-A, VEGF-B, Thrombospondin-2, Flt 4) • b) HIC (VEGF-C, PDGF-C, Neuropilin-1, Delta-like-ligand 4/DLL 4, BV 8, p 53 and Timidine Phosphorilase). Jubb, Clin Cancer Res, 2011
A = low endothelial Delta-like ligand-4 expression B = high endothelial Delta-like ligand-4 expression.
Clinical trials assessing in-situ biomarkers in relation to the efficacy of bevacizumab R. Danesi Il ruolo dell'angiogenesi 35
Biomarkers. Conclusions: 1) The absence of a target seems define a target in itself. 2) For a high percentage of triple-negative tumours we may hypotize an angiogenesis addiction. 3) Anti-VEGf agents seem work well in all the subtypes of triplenegative tumours.
BIOMARKERS. Roberto Bordonaro Struttura Complessa di Oncologia Medica ARNAS Garibaldi Catania Thanks for your kindly attention…
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