1 / 38

BIOMARKERS. Roberto Bordonaro Struttura Complessa di Oncologia Medica ARNAS Garibaldi Catania

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 ” .

raymond-riley
Download Presentation

BIOMARKERS. Roberto Bordonaro Struttura Complessa di Oncologia Medica ARNAS Garibaldi Catania

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. BIOMARKERS.Roberto BordonaroStruttura Complessa di Oncologia MedicaARNAS GaribaldiCatania

  2. 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, PgR and Her2. They also reflect the moment when the cell develops the tumor phenotype.

  3. image by Katie Vicari, from Prat and Perou, Nature Medicine, Aug;15(8):842-4 (2009)

  4. Her2+ve tumours Her2+ve / ER and/or PgR+ve ER and/or PgR+ve image by Katie Vicari, from Prat and Perou, Nature Medicine, Aug;15(8):842-4 (2009)

  5. Her2+ve tumours Her2+ve / ER and/or PgR+ve ER and/or PgR+ve image by Katie Vicari, from Prat and Perou, Nature Medicine, Aug;15(8):842-4 (2009)

  6. 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 TP53-mutations, some are BRCA1-mut carriers). • They have high proliferative rate and a poor prognosis (in terms of poor relapse-free and/or overall survival).

  7. Claudin-low Subtype 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 HER2 Basal Luminal Proliferation Claudin 3 Claudin 4 Claudin 7 E-Cadherin

  8. Claudin-low Subtype 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 HER2 Basal Luminal Proliferation Claudin 3 Claudin 4 Claudin 7 E-Cadherin

  9. Phenotypic and Molecular Characterization of the Claudin-low Intrinsic Subtype of Breast Cancer, Prat et al., Breast Cancer Res. 2010 Sep 2;12(5):R68. (PMID: 20813035)

  10. Basal-like phenotype • (75% of TNBC cancers; 10-20% • of BC); • ● >50% TP53-mutated; • ● high proliferative rate (RB loss) •  DNA-recombination defects • related to BRCA1-mutations. HER2 CRYAB ID4 EGFR/HER1 c-KIT Keratin 5 Keratin 17 P-Cadherin Luminal Proliferation

  11. Basal-like phenotype • (75% of TNBC cancers; 10-20% • of BC); • ● >50% TP53-mutated; • ● high proliferative rate (RB loss) •  DNA-recombination defects • related to BRCA1-mutations. HER2 CRYAB ID4 EGFR/HER1 c-KIT Keratin 5 Keratin 17 P-Cadherin Luminal Proliferation

  12. Deconstructing the Molecular Portraits of Breast Cancer, Prat and Perou, Molecular Oncology, Nov 24, 2010(PMID: 21147047)

  13. BRCA1- 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 HER2-negative C-myc amplified Medullary Pushing margins DCIS less common Lymphocytic infiltrate TP53 mutations Basal phenotype EGFR expression X-chromosome inactivation pattern Sensitivity to DNA damage

  14. BRCA1 Is Key to Repairing DNA Damage Several DNA damage response pathways exist: • Homologous recombination (HR) • DEPENDS ON BRCA1 • Base excision repair (BER) • DEPENDS ON PARP • Nucleotide excision repair (NER) • Mismatch repair (MMR)

  15. Platinum-sensitivity of BRCA1mut – TNBCs • 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

  16. Interesting biological analysis; small series (28), only two BRCA1 mutation carriers enrolled.

  17. Biomarkers. • Are there any biological characteristic expressed by triple-negative tumours that may influence the therapeutic choice?

  18. 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 CXCL12 Immune Cell 13-gene VEGF- signature

  19. 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 CXCL12 Immune Cell 13-gene VEGF- signature

  20. Hypoxia-related Features andBasal-like Tumors 13-gene VEGF-signature VEGF Expression • Antiangiogenic approaches work in TNBC at least as well as other subtype, possibly more. Hu, BMC Medicine 2009

  21. A compact VEGF signature associated with distant metastases and poor outcomes, Hu et al. BMC Medicine 2009, doi:10.1186/1741-7015-7-9

  22. 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)

  23. 679 consecutive Bc patients; among them, 87 (13%) where ER, PgR and Her2-ve. TN patients had significantly higher VEGF activiity: mValue = 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 PgR and/or Her2+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). Her2 overexpression was associated with high levels of VEGF (p <.001).

  24. dDFS RFS OS BCCS Linderholm, AnnOncol 2009

  25. Linderholm, Ann Oncol 2009

  26. Biomarkers. • But, which chemoterapeutic agents shown activity and/or efficacy when administered to triple-negative breast cancer?

  27. Pathologic Response to Anthracycline/Taxane by Subtype 369 patients from 3 neoadjuvant datasets Modified PAM50 Overall pCR rate = 22% (82/369) Majority of TNBC Courtesy C. Perou

  28. Chemotherapy Advances BenefitTriple Negative ER Negative ER Positive • Docetaxel – Same findings (ECOG/Geicam) • Anthracycline added to CMF paclitaxel paclitaxel No paclitaxel No paclitaxel HER2 NEG paclitaxel paclitaxel No paclitaxel No paclitaxel HER2 POS (CALGB 9344: AC +Paclitaxel) Hayes, NEJM 2008; Perez, BCRT 2010; Di Leo, SABCS 2008

  29. Anthracycline versus Non-AnthracyclineMA.5 Revisited CEF CMF Biologic # 5 Year # 5 Year p Subtype OS OS Luminal A 62 93% 71 90% Luminal NOS 36 94% 26 85% Luminal B 67 71% 65 71% Luminal B 21 71% 27 44% <0.001 HeR2+/ER- 20 55% 23 30% Basal by IHC 35 51% 35 71% <0.0001 TNBC Non-Basal 9 65% 20 63% Intriguing, although retrospective and small Cheang M et al, ASCO 2009

  30. Responsiveness to Conventional Chemotherapy Basal-like / triple negative: Often responsive If pCR achieved = good outcome! Nonresponse = poor outcome

  31. Predicting Markers of Clinical Benefit • VEGF genotypes associated with improved OS in E2100. • 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

  32. Biomarkers. • AVF2119: 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, Flt4) • b) HIC (VEGF-C, PDGF-C, Neuropilin-1, Delta-like-ligand-4/DLL4, BV8, p53 and Timidine Phosphorilase). Jubb, Clin Cancer Res, 2011

  33. A = low endothelial Delta-like ligand-4 expression B = high endothelial Delta-like ligand-4 expression.

  34. Clinical trials assessing in-situ biomarkers in relation to the efficacy of bevacizumab Il ruolo dell'angiogenesi

  35. Biomarkers. Conclusions: • The absence of a target seemsdefine a target in itself. • For a high percentage of triple-negative tumourswemayhypotize an angiogenesisaddiction. • Anti-VEGf agents seem work well in all the subtypes of triple-negative tumours.

  36. BIOMARKERS.Roberto BordonaroStruttura Complessa di Oncologia MedicaARNAS GaribaldiCatania Thanks for your kindly attention…

More Related