1 / 44

Carcinoma del surrene: novità in tema di prognosi e terapia

Carcinoma del surrene: novità in tema di prognosi e terapia. M. Terzolo, A. Ardito, F. Daffara, B. Zaggia, A. Pia, G. Reimondo, C. Fiori, A. Ferrero, P. Sperone, M. Volante, F. Porpiglia, M. Papotti, A. Berruti. Medicina Interna 1 a Indirizzo Endocrinologico AOU San Luigi Orbassano.

aileen
Download Presentation

Carcinoma del surrene: novità in tema di prognosi e terapia

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. Carcinoma del surrene: novità in tema di prognosi e terapia M. Terzolo, A. Ardito, F. Daffara, B. Zaggia, A. Pia, G. Reimondo, C. Fiori, A. Ferrero, P. Sperone, M. Volante, F. Porpiglia, M. Papotti, A. Berruti Medicina Interna 1 a Indirizzo Endocrinologico AOU San Luigi Orbassano

  2. Prognostic parameters : definitions and limitations Specify the population analyzed, the time of initiation and the endpoint • Prognostic parameters: • Parameters correlated with survival are sought Study starts at the time the cancer is ascertained Tumor diagnosis Therapeutic intervention Cancer diagnosis Survival • Predictors of response: • Parameters correlated with tumor response are sought • Study starts at the time of treatment and • Diagnostic parameters: • Parameters correlated with recurrence are sought • Study starts at the time the tumor (benign, malignant) is diagnosed

  3. PROGNOSTIC PARAMETERS: 1.ROBUST : reproducible, applicable, precise 2.PREVALENT 3.VALIDATED 4.INFORMATIVE = PROGRESS COMPARED TO THE MOST WELL ESTABLISHED PROGNOSTIC CLASSIFICATION

  4. Prognostic factorsDemographicClinicalPathologicalMolecular

  5. Survival by gender, age and secreting status n=76 men Proportion of Surviving n=109 women N= 185 patients P= NS Months n=95 non-functioning ACCs n= 90 functioning ACCs Proportion of Surviving Proportion of Surviving n=94 pts <45 yrs n= 91 pts >45 yrs Months Months

  6. Survival for patients with cortisol-secreting ACC treated (red) or not treated (black) with o,p’DDD (D)

  7. RECURRENCE-FREE SURVIVAL

  8. Progress within TNM stage: stage III-IV Hormonal secretion <0.01 DFI > 2yrs <0.02 Gender NS PS NS Number of tumoral organs NS (0.09) Berruti A et al. Endoc Rel Cancer 2005 Variables p (multivariate)

  9. Icard et al., 2001 Shulick & Brennan, 1999

  10. Disease-specific survival stratified according to the new 2008 ENS@T staging classification for ACC on 416 patients. Fassnacht et al., 2009 Excluding stage I patients who suffered tumor spillage during surgery, disease specific survival was significantly better than for stage II (p=0.012).Survival of patients with incompletely resected stage II ACC is similar or worse than that of patients with completely resected stage III disease.

  11. ENSAT staging • Stage I ACC ≤ 5cm • Stage II ACC > 5cm • Stage III ACC at least one of the following: • N1 • T3 (adipose tissue)-T4 (adjacent organs) • Thrombus within the renal vein or the vein cava • Stage IV distant metastasis Fassnacht M et al Cancer 2008 : 416 patients, German ACC registry

  12. Progress in TNM staging: ENSAT staging has been validated ENSAT I: <=5, II: > 5 centimeters intra-adrenal, III: others, IV: distant metastasis

  13. Resecability of the primary but also the R status are prognostic M status: S Size : NS N status: S Surgery adjacent organ : S R status: S Grade : S Bilimoria KY et al. Cancer 2008 : US-NCDB registry, 2982 ACC (>=8cm) patients

  14. n = 3482 Margin status Successful primary surgery has a dominant role on disease-specific survival. Schulick & Brennan, 1999 Bilmoria et al., 2008

  15. R0 : margins not involved R1 : margins microscopically involved R2 : margins macroscopically involved R0 resection does not prevent recurrence German ACC Registry, 2008 Courtesy of M. Fassnacht

  16. The popular Weiss system combines 9 parameters, including: “dark” cells diffuse archit necrosis 3 Struc-tural 3 invasion related capsule veins sinusoids 3 Cytolo-gical 9 atypia mitotic count atypical mit

  17. ANY PROGNOSTIC ROLE ?? PROGNOSTIC VALUE OF MORPHOLOGICAL PARAMETERS The impact of each pathological parameter was considered, with regard to: 1- therapy-response prediction 2- prognostic significance (low & high risk ACC groups)

  18. MULTIVARIATE ANALYSIS p Stage 1-2/3-40.03 Mitoses <9/>9 0.02 DFS p Stage 1-2/3-40.006 Mitoses <9/>9 0.001 OS Prognostic value of stage & mitoses

  19. Overall Survival Completi Censurati 0.0 0 50 100 150 200 250 300 350 400 Tempo Overall Survival in 92 pts with ACC 1.0 0.9 P<0.005 0.8 0.7 0.6 Proportion Surviving Proporzione Cumulata Sopravviventi 0.5 0.4 < mitosis 9 and stage I, II 0.3 mitosis >9 and stage I, II or mitosis 9 and stage III, IV < mitosis > 9 and stage III, IV 0.2 0.1 Months Volante et al., 2009

  20. Disease specific survival: -Multivariate analysis- Mets at diagnosis p<0.001 Adjacent organ inv. p=0.004 Mitotic rate p=0.04 Stojadinovic et al., 2002 Assiè et al., 2007

  21. ACC prognostic stratification towards combination Miller et al. 2010 91 ACC Stage (ENSAT) and mitotic count identify 4 prognostic subgroups Volante M et al . 2009 92 ACC Stage (UICC) and mitotic count identify 3 prognostic subgroups I+II LG II HG + III LG III HG IV HG or LG : mitosis > Or < 20/50 HPF

  22. Ki-67

  23. Disease-free survival by Ki-67 in the German ACC registry Courtesy of M. Fassnacht

  24. Recurrence-Free Survival Completed Censored Ki67 10% Proportion Recurrence FreeSurviving p=0.001 Ki67 >10% Months

  25. SF-1 2010;95:E161-71 detectable in 158/161 (98%) ACC samples Strong SF-1 protein expression significantly correlated with poor clinical outcome: tumor stage-adjusted hazard ratio for death 2.46 and for recurrence 3.91 SF-1 expression is a stage-independent prognostic marker in patients with ACC. SF-1 Ab: courtesy of dr E Lalli

  26. ANY PROGNOSTIC ROLE ?? PROGNOSTIC VALUE OF MORPHOLOGICAL PARAMETERS Some parameters (mitoses) are also prognostic and are implemented by markers (Ki67, SF-1, …..) and GEP Predictive factors of response to treatment have been identified (eg ERCC1) and others are under investigation

  27. De Reynìes et al., 2009 The combined expression of BUB1B and PINK1 was the best predictor of overall survival and remained significant after adjusting for MacFarlane staging.

  28. GEP 2875 differentially regulated genes in ACA vs ACC. Many related to cell cycle & invasion CSTA, RALA, VAC14, APOOL, MOSPD1, PRKD3, TFE3, PRR3, C5orf32, KiF5B

  29. GEP Gene expression profiling by transcriptome analysis led to ACC being divided into two groups of tumors with very different outcomes. Somatic inactivating mutations of the tumor suppressor gene TP53 and activating mutations of the proto-oncogene β-catenin (CTNNB1) are the most frequent mutations identified in ACC. In 51 adult sporadic ACCs, all TP53 and CTNNB1 mutations seemed to be mutually exclusive and were observed only in the poor-outcome ACC group. 52% of the poor-outcome ACC group had TP53 or CTNNB1 mutations and 60% had abnormal p53 or -catenin immunostaining. Cancer Res. 2010;70:8276-81

  30. Biomarkers : protein expressiona bridge towards therapy ? Median OS : 14 vs 49.8 mos Median OS : 23 vs 110 mos Fig 2A Sbiera S et al. JCEM 2010 : 127 multistage ACC (ENSAT), SF1 high expression is associatied with a poor outcome (p=.006; HR 2.46, 95%IC :1.3-4.6) together with the stage Gaujoux S et al. Clin Ca Res 2011 : 79 multistage ACC (ENSAT) positive b-catenin nuclear staining is associatied with a poor outcome (p=.01; HR 2.3, 95%IC :1.2-4.5)together with the stage

  31. Predictive markers ERCC1 Adam P, ..., Fassnacht M. Mod Pathol. 2010 Aug 6. Epub EGFR expression in 128/169 ACC and 1/31 ACA (by IHC, but no mutations). No significant correlation with clinical outcome. No role as predictor?? EGFR ? Doghman M et al, Cancer Res. 2010;70:4666-75. miR-99a & miR-100 coordinately regulate IGF/mTOR pathway in childhood ACT. Everolimus greatly reduced ACT cell line growth under possible miRNA regulation. Predictive role for mTOR pathway inhibiting drugs in ACC? IGF mTor

  32. Ronchi et al., 2009

  33. PLASMA CONCENTRATIONS OF MITOTANE PREDICTED TUMOR RESPONSE IN 91 PATIENTS WITH ADVANCED ACC TREATED WITH MITOTANE ± CHEMOTHERAPY

  34. At the time of therapeutic initiation plasma mitotane levels and objective response are the strongest predictors of survival Malandrino L et al. ERC 2010

  35. Take-home messages • Prognosis of ACC is still heterogeneous • Critical multistep characterization of : • Stage, R status, proliferative index, plasma mitotane level, objective response, comorbidity, hormonal status • Validation of new parameters • a lot of methodology • to be done against stage and proliferative index • Progress in biomarkers means well characterized patients and bio-bank registries as a prerequisites: collect ACC tumor and join national and European networks Modified from Baudin, 2011

  36. Donna di 43 anni Buone condizioni di salute. In seguito a colica renale effettua US che evidenzia massa surrenalica, per cui viene richiesta TC addome. Nessuna evidenza di secrezione ormonale.

  37. Donna di 43 anni • SURRENECTOMIA LAPAROSCOPICA • SURRENECTOMIA LAPAROTOMICA ….decide il chirurgo!

  38. Donna di 43 anni Intervento per via laparoscopica Istologico: carcinoma corticosurrenalico Margini liberi Dimensioni: 65x45x50 mm Peso: 208 g Weiss: 5 Mitosi: 12/50 HPF Ki-67: 25% ….MITOTANE • TERAPIA ADIUVANTE CON MITOTANE • SOLO FOLLOW-UP

  39. Donna di 45 anni Posta in terapia adiuvante con mitotane. Terapia relativamente ben tollerata con mantenimento di valori >14 mg/l nella maggior parte delle misurazioni. Dopo 18 mesi, evidenza di recidiva locale in sede di pregressa surrenectomia di circa 25 mm. ….CHIRURGIA • TERAPIA MEDICA (MITOTANE/CHEMIO) • RE-INTERVENTO

  40. Donna di 45 anni Istologico: recidiva di carcinoma surrenalico Asportazione apparentemente completa ….MITOTANE • MITOTANE • CHEMIOTERAPIA

  41. GRAZIE PER L’ATTENZIONE

More Related