Medical Students 2011 - J.B. Vermorken - GYNAECOLOGICAL CANCER SESSION - Endometrial Cancer
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Medical Students 2011 - J.B. Vermorken - GYNAECOLOGICAL CANCER SESSION - Endometrial Cancer
- 1. Endometrial Cancer Clinical Presentation, Diagnosis, Staging (1) Treatment (2) Jan B. Vermorken, MD, PhD Department of Medical Oncology Antwerp University Hospital Edegem, Belgium ESO student course, Ioannina, 2011
- 2. Uterine Corpus Cancer Classification Approximate Tumor type Frequency (%) Epithelial tumors (endometrioid, papillary 90 endometrioid, papillary serous, clear cell, mucinous) Mesenchymal tumors (endometrial stroma sar- 5 coma, leiomyosarcoma, other nonspecific sarcomas) Mixed tumours (malignant mixed Müllerian, 3 adenosarcoma) Secondary tumors (metastasis, direct local 2 extension: cervix, ovary, colon)
- 5. Endometrial Cancer: Pathology and Biology * Include also: adenocantoma, adenosquamous, undiff., squamous, mucinous Type I (70-80%)* Type II (10-20%) Histotype endometrioid adenoca. papillary serous; clear cell Precursor lesions atypical hyperplasia endometrial CIN Hormone sensitivity yes no Grading low high Initial stage early 70% advanced 60% Behavior favorable aggressive Recurrence local abdominal, lymphatic Molecular alterations MSI with MMR defects (20%) PTEN deletion (80%) KRAS, β caterin mut (40%) PI3K mut (39%) p53 mut (90%) HER2 overexpress. (45%) amplific. (70%) 5 yr survival 85% 43%
- 6. Endometrial Cancer: FIGO Staging Surgical & Pathological Old FIGO staging New FIGO staging Pathological assessment includes: M, cervical involvement, tumor size and location, extension to fallopian tubes and ovaries, grade and hystological subpypes, lymphovascular space invasion (LVSI), nodal status 75% stage I
- 8. Endometrial Cancer Distribution by stage Stage Number Percent I 6260 71.1 II 1071 12.2 III 1190 13.5 IV 286 3.2 Total 8807 100.0 FIGO Annual Report, 2006
- 15. Endometrial Cancer - Cytotoxic Therapy Chemonaive patients Agent # Pts % RR % CR Cyclofosfamide 23 9 - Ifosfamide 65 22 8 Doxorubicin 196 25 10 Epirubicin 24 25 8 Cisplatin 95 25 5 Carboplatin 76 30 7 Paclitaxel 28 36 14 Vermorken JB, Baekelandt M, 2004
- 16. Endometrial Cancer – Cytotoxic Therapy Randomized Studies Regimen # Pts % RR % CR MS (mo) Doxorobucin (D) 122 27 8 + 9 D + cisplatin 101 45 22 + 9 Doxorubicin (D) 71 (47) 19 13 8.0 * D + cisplatin 74 (53) 33 21 13.0 * D + cisplatin (P) 266 + 33 ** 7 50% (12 mo) DP + paclitaxel 57 ** 22 58% (12 mo) * Intent-to-treat analysis (p = 0.36); + eligible pts randomized. ** p < 0.001
- 18. mTOR Inhibitors in Endometrial Cancer Route Dose 1 st line activity 2nd line activity Temsirolimus NCIC IND 160 IV 25 mg Q wk 25% RR (60% SD) 7% RR (2/27) Evirolimus PO 10 mg QD ND 0% RR CBR 40% Ridaforolimus Colombo et al IV 12.5 QDx5 Q2 wk ND 9% RR (4/45) CBR 30% Ridaforolimus NCIC IND 192 PO 40 QDx5 Q wk RR endpoint Ridaforolimus NCIC CTG/EN8 PO 40 QDx5 Q wk vs 160 mg/day MA* PFS endpoint *megestrol acetate
- 19. mTOR Inhibition May Enhance the Antitumor Effects of Other Therapies mTOR Inhibition Chemotherapy Radiation EGFR Inhibitors Antiestrogens Antiangiogenics
Notas del editor
- Growth-stimulating signals originating from within and outside the cell are integrated through mTOR into processes that maintain cell viability and stimulate cell growth, cell division, and angiogenesis. mTOR is a sensor that acts as a biochemical switch, ensuring that supplies of energy and nutrients in the cell are sufficient to support these processes 1,2 In cancer cells, one or more of the proteins shown upstream of mTOR may be deregulated, and this loss of regulation contributes to, and in some cases drives, the malignancy. These include overproduction of hormones, cytokines, and growth factors and aberrant expression of growth factor receptors and signaling molecules, such as PI3-K, PTEN, Akt, and TSC1/2 (and LKB1, which is not shown). Aberrant signaling in parallel signaling pathways also affects signaling through mTOR because these pathways are connected to the mTOR pathway. These connections are referred to as “cross-talk” and involve the Ras/Raf/MAPK pathway and Abl signaling 2-5 References Bjornsti and Houghton. Nat Rev Cancer . 2004;4:335-348. Crespo and Hall. Microbiol Mol Biol Rev . 2002;66:579-591. Huang et al. Cancer Biol Ther . 2003;2:222-232. Mita et al. Clin Breast Cancer. 2003;4:126-137. Wullschleger et al. Cell. 2006;124:471-484.
- Cancer therapy with mTOR inhibition may potentially be used with other approaches to cancer monotherapy or multimodality therapy. Several multiagent combinations are being investigated in clinical trials. The figure shows combinations for which a rationale has been developed in preclinical studies