Endometrial Cancer Clinical Presentation, Diagnosis, Staging (1) Treatment (2) Jan B. Vermorken, MD, PhD Department of Med...
Uterine Corpus Cancer Classification Approximate Tumor type Frequency (%) Epithelial tumors (endometrioid, papillary 90 en...
Endometrial Cancer <ul><li>Pathology Subtypes </li></ul><ul><li>Endometrioid 60% </li></ul><ul><li>Adeno-acanthoma 22% </l...
<ul><li>The most common gyne cancer in Western countries </li></ul><ul><li>Incidence 15/100.000 women/yr Europe </li></ul>...
Endometrial Cancer: Pathology and Biology * Include also: adenocantoma, adenosquamous, undiff., squamous, mucinous Type I ...
Endometrial Cancer: FIGO Staging Surgical & Pathological Old FIGO staging New FIGO staging Pathological assessment include...
Endometrial Cancer How does it spread <ul><li>Routes </li></ul><ul><li>Direct extension to adjacent structures (most commo...
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 ...
Endometrial Cancer Surgery is (still) the cornerstone of treatment <ul><li>Hysterectomy + BSO is the cornerstone in the th...
Endometrial Cancer: Risk Categories for Adjuvant Therapies Background <ul><li>Risk factors for node invasion: stage, age, ...
Endometrial cancer: Adjuvant chemotherapy <ul><li>Not standard, but in study </li></ul><ul><li>Can be considered  for HR p...
Endometrial Cancer Progestin Therapy (1) <ul><li>As primary treatment  in case of atypical hyperplasia or grade 1 EC in pr...
Endometrial Cancer  Progestin Therapy (2) <ul><li>As treatment for advanced and recurrent disease </li></ul><ul><li>1984: ...
Endometrial Cancer Other hormonal therapies <ul><li>Tamoxifen  in progestin failures    22% RR </li></ul><ul><li>Tamoxife...
Endometrial Cancer - Cytotoxic Therapy Chemonaive patients Agent # Pts % RR % CR Cyclofosfamide 23 9 - Ifosfamide  65 22 8...
Endometrial Cancer – Cytotoxic Therapy Randomized Studies Regimen # Pts % RR % CR MS (mo) Doxorobucin (D) 122 27 8 +  9 D ...
Growth Factors and the mTOR Pathway Protein Production 4E-BP1 PTEN S6 elF-4E Growth Factors IGF-1, EGF, TGF α , VEGF, etc ...
mTOR  Inhibitors in Endometrial Cancer Route Dose 1 st  line activity 2nd line activity Temsirolimus NCIC IND 160 IV 25 mg...
mTOR Inhibition May Enhance the Antitumor Effects of Other Therapies  mTOR Inhibition Chemotherapy Radiation EGFR Inhibito...
Endometrial Cancer Conclusions <ul><li>No routine adjuvant hormonal or chemotherapy </li></ul><ul><li>Hormonal therapy fir...
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Medical Students 2011 - J.B. Vermorken - GYNAECOLOGICAL CANCER SESSION - Endometrial Cancer

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  • 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
  • Medical Students 2011 - J.B. Vermorken - GYNAECOLOGICAL CANCER SESSION - Endometrial Cancer

    1. 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. 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)
    3. 3. Endometrial Cancer <ul><li>Pathology Subtypes </li></ul><ul><li>Endometrioid 60% </li></ul><ul><li>Adeno-acanthoma 22% </li></ul><ul><li>Adenosquamous 7% </li></ul><ul><li>Clear cell 6% </li></ul><ul><li>Serous (Papillary) 4.5% </li></ul><ul><li>Secretory 1.5% </li></ul><ul><li>Mucinous 1% </li></ul>
    4. 4. <ul><li>The most common gyne cancer in Western countries </li></ul><ul><li>Incidence 15/100.000 women/yr Europe </li></ul><ul><li>Mortality 4-5/100.000 women/yr </li></ul><ul><li>80-90% post menopausal; 5% in <40 yrs old </li></ul><ul><li>Peak incidence 60 yrs </li></ul><ul><li>Aetiological factors : unopposed / excessive oestrogen exposure </li></ul><ul><li>Predisposing factors : nulliparity, early menarche/late menopause </li></ul><ul><li>obesity, diabetes, hypertension </li></ul><ul><li>treatment with tamoxifen </li></ul><ul><li>Genetic susceptibility : Lynch type II syndrome </li></ul>Endometrial Cancer: Epidemiology
    5. 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. 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
    7. 7. Endometrial Cancer How does it spread <ul><li>Routes </li></ul><ul><li>Direct extension to adjacent structures (most common) </li></ul><ul><li>Transtubal passage of exfoliated cells </li></ul><ul><li>Lymphatic dissemination (pelvic LN, PAO LN) (also responsible for vaginal metastases) </li></ul><ul><li>Hematogenous dissemination (lung, liver, brain, bone and other) </li></ul>
    8. 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
    9. 9. Endometrial Cancer Surgery is (still) the cornerstone of treatment <ul><li>Hysterectomy + BSO is the cornerstone in the therapy of endometrial carcinoma* </li></ul><ul><li>The uterus should be removed whenever feasible </li></ul><ul><li>Hysterectomy enhances twofold the chances of cure </li></ul><ul><li>Uterus pathology provides the best information on the risk factors of this tumor: histologic grade and myometrial invasion </li></ul><ul><li>*Mangioni C, 1988 </li></ul>
    10. 10. Endometrial Cancer: Risk Categories for Adjuvant Therapies Background <ul><li>Risk factors for node invasion: stage, age, histotype, grade, M, LSVI </li></ul><ul><li>Risk categories </li></ul><ul><li>Low risk (55%): IA, endometrioid, gr 1-2 </li></ul><ul><li>Intermediate risk (30%): IB gr 1-2, IA gr 3, endometrioid, no LSVI </li></ul><ul><li>High risk (15%): IB gr 3, II-III, nonendometrioid any stage </li></ul>
    11. 11. Endometrial cancer: Adjuvant chemotherapy <ul><li>Not standard, but in study </li></ul><ul><li>Can be considered for HR patients and /or with nodal metastases </li></ul><ul><li>Evaluated in combination with RT (PORTEC 3 study: IB-C gr 3, serous IB-III, IIIA, IIIC; EBRT vs EBRT + CDDP->4xTC) </li></ul><ul><li>Preferred regimen carbo/paclitaxel (GOG249 study: I-II HR, I-II serous, CC; EBRT vs VBT and 3xTC) </li></ul><ul><li>Retrospective data of efficacy of TC is available in clear cell, serous papillary tumors </li></ul><ul><li>TC is comparable to TAP in terms of PFS, OS in bluky disease </li></ul>
    12. 12. Endometrial Cancer Progestin Therapy (1) <ul><li>As primary treatment in case of atypical hyperplasia or grade 1 EC in premenopausal women desiring to preserve fertility </li></ul><ul><li>As adjuvant treatment in stage I and II disease. Several negative studies. May be a tendency towards fewer cancer-related deaths in high-risk patients. However, high-risk means less chance of PR + tumors </li></ul>
    13. 13. Endometrial Cancer Progestin Therapy (2) <ul><li>As treatment for advanced and recurrent disease </li></ul><ul><li>1984: compiled data 34% RR, 13% NC </li></ul><ul><li>duration of response 16-28 months (Kaupilla) </li></ul><ul><li>Later studies found only 15.8% and 11.2% RR </li></ul><ul><li>Type of progestin and route of administration do not seem to be of major importance </li></ul><ul><li>GOG trial: 200 mg vs 1000 mg/d oral MPA  </li></ul><ul><li>no difference (Thigpen, 1991) </li></ul>
    14. 14. Endometrial Cancer Other hormonal therapies <ul><li>Tamoxifen in progestin failures  22% RR </li></ul><ul><li>Tamoxifen can induce PR expression  rationale for combined or sequential treatment with tamoxifen and progestational agent </li></ul><ul><li>Leuprorelin or goserelin  35% RR (6/17) </li></ul><ul><li>leuprorelin 0% (0/25) </li></ul><ul><li>Anastrazole  phase II study 9% RR </li></ul>
    15. 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. 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
    17. 17. Growth Factors and the mTOR Pathway Protein Production 4E-BP1 PTEN S6 elF-4E Growth Factors IGF-1, EGF, TGF α , VEGF, etc Cell Growth and Proliferation Angiogenesis mTOR Oxygen, energy, and nutrients <ul><li>mTOR </li></ul><ul><ul><li>Intracellular protein </li></ul></ul><ul><ul><li>Central controller of cell growth and proliferation </li></ul></ul><ul><li>mTOR signaling is often deregulated in cancer </li></ul><ul><li>Downstream inhibition of mTOR has potential for </li></ul><ul><ul><li>Antiproliferative effects on tumor cells </li></ul></ul><ul><ul><li>Angiogenesis inhibition </li></ul></ul><ul><ul><li>Enhancement of the effects of chemotherapy </li></ul></ul>TSC2 TSC1 Akt/PKB PI3-K S6K1 Ras/Raf Abl ER Ras/Raf pathway kinases
    18. 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. 19. mTOR Inhibition May Enhance the Antitumor Effects of Other Therapies mTOR Inhibition Chemotherapy Radiation EGFR Inhibitors Antiestrogens Antiangiogenics
    20. 20. Endometrial Cancer Conclusions <ul><li>No routine adjuvant hormonal or chemotherapy </li></ul><ul><li>Hormonal therapy first choice for recurrence </li></ul><ul><ul><li>Progestins: 200 mg/d MPA </li></ul></ul><ul><ul><li>Tamoxifen: 20-30 mg/d </li></ul></ul><ul><li>Chemotherapy for hormone failures </li></ul><ul><ul><li>Standard: doxorubicin + cisplatin </li></ul></ul><ul><ul><li>Alternative: paclitaxel + carboplatin </li></ul></ul><ul><li>Molecular targeted therapy: experimental </li></ul>

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