Lessons learned from translational work on the PORTEC trials Gynecologic Cancer InterGroup Translational Research Brainstorming October 2016 Lisbon Tjalling Bosse Department Pathology LEIDEN UNIVERSITY MEDICAL CENTER
Lessons from PORTEC-1,-2, -3 and -4 #1 … #2 … #3 … #4 …
Interobsever variability in GYNpathology review is an issue “ Clinically significant diagnostic discrepancies in the field of gyneacologic pathology occur more frequently than in other areas of pathology. ” Mandatory second opinion in surgical pathology referral material: Clinical consequences of major disagreements. Manion et al., Am J Surg Path 2008
Interobserver variability in endometrial cancer Gilks et al, AJSP 2013
Results retrospective PORTEC-2 review Original Review Agreement N % N % % Kappa Non-endometrioid 0 0 12 3 0 Grade 62.2 0.33 1 175 49 286 81 2 158 45 33 9 3 22 6 36 10 Myometrial invasion 91.7 0.67 <50% 46 13 60 17 3 3 ≥ 50% 315 87 301 83 2 LVSI 90.7 0.54 present 38 10 46 13 absent 328 90 320 87 2 Cervical gland. inv. 93.2 0.62 1 1 present 45 12 28 8 absent 320 88 337 92
Results retrospective PORTEC-2 review Overal Survival in PORTEC-2 Before central review After central review • PORTEC-1: 23,6% not eligible after retrospective path. review • PORTEC-2: 14% not eligible after retrospective path. review
Upfront pathology review PORTEC-3 (NL+UK) 8.3% not HighRisk De Boer, IGCS 2016 poster
Pathology review in the PORTEC studies • PORTEC-1: 23,6% not eligible in retrospective path review • PORTEC-2: 14% not eligible in retrospective path review • PORTEC-3: 8,3% not eligible in prospective path review Con’s prospective path review: • Logistics, logistics and logistics (timing, transport and communication) Pro’s prospective path review: • Improves clinical trials, by “clean” inclusion • Seems especially critical in trials with toxic treatment • Teaching tool, identifies knowledge gaps • Prospective central biobank collection De Boer, IGCS 2016 poster
Biobanking the FFPE blocks from the PORTEC-trials Trial Year Inclusion Randomisation FFPE Biobank PORTEC-1 1990-97 Low Risk EBRT vs NAT 477/715 (67%) PORTEC-2 2000-06 Intermediate Risk EBRT vs BT 384/427 (90%) PORTEC-3 2007-13 High Risk EBRT vs RT+CT 430/686 (62%) PORTEC-4a 2016- … Intermediate Risk Molecular Profiles 11/11 (100%) Obstacles • “ O ld trials”; blocks are destroyed or lost • Material exhausted for other purposes • International trials more complex Success factors • Central pathology review • Local people’s willingness to help
Lessons from PORTEC-1,-2, -3 and -4 #1 Upfront pathology review by expert gynaecological pathologists is to be preferred to ensure enrollment of the target trial population and to avoid unnecessary treatment and toxicity #2 Upfront (multi)central collection of tissue from trial patients is to be preferred to ensure an optimal trial-tumorbiobank #3 … #4 …
What are we going to do with that biobank? Identifying prognostic and predictive biomarkers, to personalize treatment. Reducing over- and undertreatment. 1. PRACTICAL (cheap and quick) 2. EFFECTIVE IN PREDICTING BIOLOGIC BEHAVIOR 3. REPRODUCIBLE (easy)
Pathology assessment is MORE than histotype alone The ‘Big Five’ of endometrial cancer
Pathology assessment is more than histotype Tumortype Endometrioid Serous Clearcell
Pathology assessment is more than histotype Tumortype Grade Endometrioid Gr. 1 <5% solid Serous Gr. 3 >50% solid Clearcell
Pathology assessment is more than histotype Myometrial Involvement Tumortype Grade Endometrioid Gr. 1 <5% solid Serous Gr. 3 >50% solid Clearcell
Pathology assessment is more than histotype Endocervical Myometrial Involvement Involvement Tumortype Grade Endometrioid Gr. 1 <5% solid Serous Gr. 3 >50% solid Clearcell
Pathology assessment is more than histotype Endocervical Myometrial Involvement Involvement Tumortype Grade LVSI Endometrioid Gr. 1 <5% solid Serous Gr. 3 >50% solid Clearcell
What is the current risk assessment? • Low Stage I Endometrioid + gr 1-2 + <50% myometrial invasion + LVSI neg Risk • Stage I Endometrioid + gr 1- 2 + ≥50% myometrial invasion + LVSI neg Low Inter Risk • High Inter Stage I Endometrioid + gr 3 + <50% myometrial invasion, regardless of LVSI status • Risk Stage I Endometrioid + gr 1-2 + LVSI positive, regardless of depth of invasion • Stage I Endometrioid + gr 3 + ≥50% myometrial invasion, regardless of LVSI status High Risk • Stage II & microscopic stage III • Non endometrioid (Serous or Clear cell, etc) • Adv Stage III bulky & IVa • M+ Stage IVB FIGO 2009 staging used LVSI assessment is important, but poorly defined LVSI assessment may requires quantification to be truly prognostic Colombo et al., Annals of Oncology 2016
Definitions used in daily practice by 6 independent well recognized GYNpathologists 1 Cohesive aggregate of tu tumor ce cells lls located inside a vascular space (defined by the presence of an en endot otheliu ium lin linin ing) and preferentially juxt xtaposed to o th the e ves essel l wall ll 2 Ca Carcin inoma cells cells adherent of vessel wall (with en endothelia ials cells cells) 3 Definite tu tumor cells cells within an en endothelia ial lin lined ed channel and no features to suggest artifactual vascular invasion 4 Presence of tu tumor cells cells in in ly lymphatic's 's or or ves essel els, which is not caused by artifacts (such as smears, retraction, etc.) 5 Tumor cell cells usually as a group or nest within a space that is covered by en endoth theli lial l cells cells and does not contain a significant number of erythrocytes 6 The presence of a tu tumor em embolus with ithin in a ves essel el (capillary or lymphatic), usually well defined, rounding up to the contour of the vessel, may or or may not ot be e attached ed to the inner surface, may include red cells or fibrin; absence of marked autolysis Manuscript in preparation 19
Proper histologic assessment is hampered by poor fixation LVSI definition : a focus of tumor cells within a (blood filled) space lined by endothelial cells. Exclude LVSI mimics • Marked autolysis • Shear/retraction artefacts • Smear/push artefacts • MELF-type invasion Criteria not required but helpful in excluding mimics • Focus outside the immediate border of the tumor • Focus surrounded by other vessels • Focus contains vascular associated lymphocytes • Multifocal, preferably >3 foci
232 uterine serous carcinoma Semiquantification: • No LVSI • Low (< 3 vessels) • Extensive (≥ 3 vessels) Winer I et al., Int J Gynecol Pathol 2014 21
(Re)assessment of LVSI from pooled PORTEC-1/-2 954 (83.6%) patients from PORTEC-1 and -2 Quantification using 2-, 3- and 4-tiered definitions of LVSI 2-tiered No No LVSI LVSI present 3-tiered No No LVSI Mild ild: a focus of LVSI was recognized around a tumor. Substantia Su ial: diffuse or multifocal LVSI was recognized around the tumor. 4-tiered No No LVSI Min inim imal: only a few lymph vascular vessels were involved on the border of the invasive front of the tumor. Moderate: more vessels were involved in a wider area surrounding the tumor. Promin inent: many vessels were diffusely involved in the deeper part of the myometrium. Bosse et al, EJC 2015
Substantial LVSI LVSI quantification and Regional Recurrence PORTEC-1 and -2 (N= 945) Substantial LVSI only (N=46) Serosa p<0.001 p=0.08 T Substantial: HR 6.1 (2.3-15.9) T Serosa Mild LVSI
What is the current risk assessment? • Low Stage I Endometrioid + gr 1-2 + <50% myometrial invasion + LVSI neg Risk • Stage I Endometrioid + gr 1- 2 + ≥50% myometrial invasion + LVSI neg Low Inter Risk • High Inter Stage I Endometrioid + gr 3 + <50% myometrial invasion, regardless of LVSI status • Risk Stage I Endometrioid + gr 1-2 + LVSI positive, regardless of depth of invasion • Stage I Endometrioid + gr 3 + ≥50% myometrial invasion, regardless of LVSI status High Risk • Stage II & microscopic stage III • Non endometrioid (Serous or Clear cell, etc) • Adv Stage III bulky & IVa • M+ Stage IVB FIGO 2009 staging used LVSI assessment is important, but poorly defined LVSI assessment may requires quantification to be truly prognostic Colombo et al., Annals of Oncology 2016
What is the current risk assessment? Manuscript in preparation
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