(1) The document summarizes the PORTEC 4A trial, which aims to evaluate molecular risk profiling to guide adjuvant treatment decisions in early-stage endometrial cancer. (2) The trial compares adjuvant vaginal brachytherapy, the current standard, to a molecular profiling-based approach that may recommend observation, brachytherapy, or pelvic radiation. (3) Based on previous studies, it is estimated that 50-55% of patients will be low risk and need only observation, 40% intermediate risk requiring brachytherapy, and 5-10% high risk needing pelvic radiation. The goal is to reduce overtreatment while maintaining local control.

1. PORTEC 4A
Journal Club
30/4/2021
Moderator :Prof Dr Pallavi VR
Dr Shruthi Shivdas Dept of Gyn Oncology, KMIO
IJGC
October 2020

2. NATURE 2013
Levine et al
Tumour samples and corresponding germline DNA were collected from 373 patients,
including 307 endometrioid and 66 serous (53) or mixed histology (13) cases
(1) an ultramutated group with unusually high mutation rates (232 3 1026 mutations
per Mb) and a unique nucleotide change spectrum;
(2) (2) a hypermutated group (18 3 1026 mutations per Mb) of MSI tumours, most with
MLH1 promoter methylation;
(3) (3) a group with lower mutation frequency (2.9 3 1026 mutations per Mb) and most
of the microsatellite stable (MSS) endometrioid cancers
(4) (4) a group that consists primarily of serous-like cancers with extensive SCNA
(copy-number cluster 4) and a low mutation rate (2.3 3 1026 mutations per Mb).
Most of the serous ( 94%) and mixed histology (62%) tumours; 12% of the endometrioid
tumours ( 24% of grade 3 and 5% of grade 1 or 2), into copy- number cluster 4
Majority of cluster 1 were grade 3 endometroid > grade 2; Cluster 2 and 3 were almost
entirely grade1 EECs.
Dr Shruthi Shivdas

3. Dr Shruthi Shivdas
7%
28%
38% 25%
Itemization of the
TCGA subgroups in
the dualistic model.

4. Dr Shruthi Shivdas
Median followup 32 mo (1-195)
Survival curves - TCGA
tumors in the
‘serous-like’
cluster (cluster
4) had
significantly
worse PFS than
tumors in the
endometrioid
cluster groups
(P=0.003, log-
rank).

5. Pathway alterations
⚫ Because of small sample size, POLE subgroup was excluded
from this analysis .
⚫ CNL - CTNNB1, KRAS and SOX17
⚫ SOX17, which mediates proteasomal degradation of b-catenin, is
mutated exclusively in the copy-number low group
⚫ ERBB2 was focally amplified with protein overexpression in
25% of the serous or serous-like tumours (94%)
⚫ PIK3 CA mutations were seen through all groups (94%), but
unlike other tumour types, they co-occurred with PTEN
mutations in the MSI and copy-number low subgroups
Dr Shruthi Shivdas

6. TCGA concluded that …....
⚫ EC has more frequent mutations in the PI3K/AKT pathway than any other tumor type studied by
TCGA.
⚫ 25% of uterine tumours classified as high-grade endometrioid by pathologists
have a molecular phenotype similar to USC, including frequent TP53 mutations
and extensive SCNA.
⚫ Clinicians should carefully consider treating these copy-number-altered
endometrioid patients with chemotherapy rather than adjuvant radiotherapy and
formally test such hypotheses in prospective clinical trials.
⚫ So also, 7% of patients diagnosed with a good prognosis cancer (EEC-Grade 1) but
with a copy-number high molecular diagnosis will now be stratified in a poorer
prognosis group.
⚫ In contrast, all patients with POLE-hypermutated tumors (6–13% of all ECs) may now
be considered good prognosis tumors, independently of the state of other prognostic
factors (e.g., histological grade or FIGO stage).
Talhouk A, et al. Molecular classification of endometrial carcinoma on diagnostic specimens is
highly concordant with final hysterectomy: Earlier prognostic information to guide
treatment. Gynecol Oncol. 2016;143(1):46-53.
Dr Shruthi Shivdas

7. TCGA - carcinosarcomas
Dr Shruthi Shivdas
In 2017, TCGA published a molecular characterization of 57 uterine
carcinosarcoma cases using the same integrated technique described for the
characterization of endometrial carcinoma in 2013
78% were serous – like / CNH
21% were endometroid / CNL
2 POLE nd 4 MSI
Unlike most other Ecs, where PTEN and p53 mutations are mutually excluside,
73 % of PTEN also had p53 mutations.
Cherniack AD, Shen H, Walter V, et al. Integrated molecular characterization of uterine carcinosarcoma. Cancer
Cell.2017;31:411‐423

8. TCGA - CCC
⚫ the most prevalent subgroups were the CNH subgroup (42.5%) and the CNL
subgroup (40.9%), almost equally distributed
⚫ MSI subgroup (9.8%) and the POLE subgroup (3.8%) were less common
⚫ So, CCC is not a homogeneous subtype, but represents at least two different
entities, which have entirely different biological behaviour and prognosis.
⚫ Therefore, it might be hypothesized that some CCCs are biologically similar to
EECs and have a better prognosis, while some are similar to USCs and have a
poorer prognosis.
⚫ This would explain the difficulties found in the prognostication of CCC and the
heterogeneity in its morphology and biological behaviour.
Travaglino et al. CCC and the TCGA . 2019
In the PORTEC-3 analysis, the frequency of recurrence among women with CCCs was
similar to that of women with EECs, and clearly lower than that of women with serous
cancers.
Dr Shruthi Shivdas

9. After TCGA….
⚫ Two research teams have subsequently developed more pragmatic
methodologies to evaluate molecular features of Ecs using surrogate IHC
markers, working in standard FFPE. These methods do not identify
molecular subgroups that are identical to TCGA but do recapitulate the
four survival curves observed in TCGA.
⚫ Molecular classification can be achieved on diagnostic endometrial samples
and accurately predicts the molecular features in the final hysterectomy
specimens, demonstrating concordance superior to grade and histotype
E Stelloo et al. Refining prognosis and identifying targetable pathways for high-risk endometrial cancer; a
TransPORTEC initiative . Modern Pathology (2015), 1–9
Talhouk A, et al. Molecular classification of endometrial carcinoma on diagnostic specimens is highly concordant with
final hysterectomy: Earlier prognostic information to guide treatment. Gynecol Oncol. 2016;143(1):46-53.
Dr Shruthi Shivdas

10. Proactive Molecular Risk
Classification tool for
Endometrial cancers
Dr Shruthi Shivdas
TransPORTEC is an
international consortium
related to the PORTEC3 trial,
established for translational
research in high-risk
endometrial cancer

11. Dr Shruthi Shivdas

12. ⚫ Molecular analysis was successful in 410 / 660 high-risk EC from the
PORTEC3 trial ,
❖ p53abn EC -23% POLEmut – 12% MMRd - 33% NSMP - 32%.
⚫ Five-year RFS was 48% for patients with p53abn EC, 98% for POLEmut EC,
72% for MMRd EC, and 74% for NSMP EC (P ,.001).
⚫ The 5-year RFS with CTRT versus RT
❖ p53abn EC was 59% versus 36% (P < .019) – significant enefit with addition of
CT to RT
❖ 100% versus 97% for patients with POLEmut EC (P < .637) – excellent survival
in both
❖ 68% versus 76% (P < .428) for MMRd EC – no benefit
❖ 80% vs 68% (P < .243) for NSMP EC- trend towards benefit
Dr Shruthi Shivdas ASCO JCO Aug 2020

13. ⚫ “Adjuvant treatment decisions based on the molecular
classification are supported; specifically, patients with p53abn EC
should be considered for adjuvant chemoradiotherapy, whereas
for those with POLEmut cancers, de-escalation of adjuvant
treatment should be considered.”
⚫ Additional studies are needed especially for MMRd and NSMP
⚫ The lack of benefit observed from the addition of a favorable
outcome with EBRT alone in stage I-II disease, as also found in
the GOG-249 trial.
⚫ a recent study reported benefit of early-stage MMRd EC from RT
compared with no adjuvant treatment.
Reijnen C, Ku¨ sters-Vandevelde HVN, Prinsen CF, et al: Mismatch repair deficiency as a predictive marker for
response to adjuvant radiotherapy in endometrial cancer. Gynecol Oncol 154:124-130, 2019
⚫ Adjuvant treatment regimens other than chemotherapy should
be explored in higher-stage MMRd ECs.
Dr Shruthi Shivdas

14. MMRd
Dr Shruthi Shivdas
Reijnen C, Ku¨ sters-Vandevelde HVN, Prinsen CF, et al: Mismatch repair deficiency as a predictive marker for
response to adjuvant radiotherapy in endometrial cancer. Gynecol Oncol 154:124-130, 2019

15. Dr Shruthi Shivdas

16. PORTEC 4a
⚫ The PORTEC-4a trial is the first study worldwide to
evaluate the clinical role of molecular risk factors in
decision making on adjuvant treatment in patients with
endometrial cancer.
⚫ PORTEC4A is a prospective, multicenter phase III study,
led by the Dutch Gynaecologic Oncology Group.
⚫ Non inferiority design
Dr Shruthi Shivdas

17. Background
⚫ Adjuvant treatment has so far been tailored to
clinicopathologic risk factors such as age, stage,
histological type, grade, depth of myometrial invasion,
and presence of LVSI. Patients are considered to be at
low- to low-intermediate risk (approximately 50% of
patients), high-intermediate risk (30%–35%), or high risk
(15%–20%) for disease recurrence.
⚫ Vaginal brachytherapy is currently recommended as
adjuvant treatment in patients with HIR endometrial
cancer to maximize local control.(PORTEC1/GOG99 +
PORTEC2)
Dr Shruthi Shivdas

18. ESMO ESGO 2016
Dr Shruthi Shivdas

19. Background
⚫ Looking now at the results of genomic profiling, there is new evidence
that one subgroup of HIR patients have been overtreated and may need
less treatment; for another subgroup, VBT might be sufficient; and a
small subgroup has been undertreated on the basis of conventional risk
factors and may need a more aggressive adjuvant treatment
⚫ Overtreatment
⚫ adjuvant brachytherapy of all patients with HIR features can still be
considered overtreatment as there are effective salvage treatments for
vaginal relapse in patients who are not previously irradiated.
⚫ pOLE mutated histologically high risk groups
⚫ Undertreatment
⚫ Molecular CNH EEC
⚫ P53 + ultra LR & LR EC
Dr Shruthi Shivdas

20. Molecular vs patho
⚫ Challenges with the current system include the lack of
inter-observer agreement in the evaluation of pathologic
features, especially on histologic type in high-grade EC,
where discrepancies reach 36% of cases examined.
⚫ In contrast, the molecular EC classification is a highly
reproducible system with strong prognostic value.
⚫ The assessment of MMR proteins and p53
immunohistochemistry are highly concordant with MSI
and TP53 mutational status, respectively, and the inter-
observer agreement is >95%.
PORTEC 3 molecular group
Dr Shruthi Shivdas

21. HR factors considered
⚫ TCGA clusters
⚫ In the long-term analysis of PORTEC 2, substantial LVSI, p53-mutations and
L1CAM expression were all strongly associated with the risk of pelvic recurrence,
distant metastasis and endometrial cancer- related survival in women with HIR.
⚫ In the small subgroup of women with high-intermediate risk endometrial
cancer with any of these unfavourable risk factors, EBRT was found to be
associates with a significantly better pelvic control than VBT.
Wortman BG, Creutzberg CL, Putter H, et al. Ten-year results of the PORTEC-2 trial for high-intermediate risk
endometrial carcinoma: improving patient selection for adjuvant therapy. Br J Cancer 2018;119:1067–74.
⚫ CTNNB1-exon 3 mutations are prognostic for higher risk of recurrence, especially
in the copy-number-low group
Stelloo E, Nout RA, Osse EM, et al. Improved risk assessment by integrating molecular and clinicopathological factors
in early-stage endometrial cancer-combined analysis of the PORTEC cohorts. Clin Cancer Res 2016;22:4215–24.
Dr Shruthi Shivdas

22. Dr Shruthi Shivdas
Wortman BG, Creutzberg CL, Putter H, et al. Ten-year results of the PORTEC-2 trial for high-intermediate risk
endometrial carcinoma: improving patient selection for adjuvant therapy. Br J Cancer 2018;119:1067–74

23. Primary objectives
To compare the rates of vaginal recurrence in women with HIR
endometrial cancer, treated after surgery with
molecular- integrated risk profile-based recommendations for either
observation, vaginal brachytherapy or EBRT to pelvis
Vs
with standard adjuvant vaginal brachytherapy
Hypothesis:
◆ The molecular-integrated risk profile- based adjuvant treatment
spares many patients the morbidity of adjuvant treatment and
reducing healthcare costs, while providing similar local control
and recurrence-free survival as current standard adjuvant
brachytherapy in patients with high-intermediate risk
endometrial cancer.
Dr Shruthi Shivdas

24. Inclusion & Exclusion Criteria
Dr Shruthi Shivdas
Sample size
⮚ 500 eligible and
evaluable
patients.
❖ At time of
publication, 366
pts included.
Lymphadenectomy, or
sentinel node
procedure are not
required but permitted
as per center standard
protocol.

25. Endpoints
⚫ The primary endpoint is vaginal recurrence.
⚫ Secondary endpoints are
⚫ RFS & OS; pelvic and distant recurrence
⚫ 5-year vaginal control (including treatment for
relapse)
⚫ adverse events and patient-reported symptoms and
quality of life
⚫ endometrial cancer-related healthcare costs.
Dr Shruthi Shivdas

26. Methodology
Dr Shruthi Shivdas
A molecular-integrated risk
model was defined by
integrating the molecular
subgroups with L1-CAM
overexpression, substantial
LVSI, and CTNNB1-exon 3
mutations.
By applying this molecular-
integrated risk profile to the
HIR cohorts of the PORTEC-1
and −2 trials, three risk
categories (favorable,
intermediate, and unfavorable)
were defined with a
significantly different RFS.

27. Dr Shruthi Shivdas
Methodology

28. Prognostic groups
⚫ Based on PORTEC analysis it is expected that approximately 50%–55% of patients with
HIR endometrial cancer have a favorable molecular profile. They need only
observation.
⚫ An estimated 40% of patients have an intermediate profile and need only vaginal
brachytherapy (21Gy in three fractions of 7 Gy each within an overall time of 2 weeks).
⚫ About 5%–10% will have an unfavorable profile and will need pelvic RT (45–48.6 Gy in
1.8–2 Gy fractions).
⚫ The question of whether this patient benefits from chemotherapy is still unclear and
should be evaluated in future studies.
Stelloo E, Nout RA, Osse EM, et al. Improved risk assessment by integrating molecular and clinicopathological factors in early-stage endometrial cancer-
combined analysis of the PORTEC cohorts. Clin Cancer Res 2016;22:4215–24.
⚫ This stratification will reduce over- and undertreatment and increase cost-effectiveness.
Dr Shruthi Shivdas

29. Prognostic groups
Dr Shruthi Shivdas
Focal LVSI is defined by the presence of a single focus around the tumor,
substantial LVSI as multifocal or diffuse arrangement of LVSI or the
presence of tumor cells in five or more lymphovascular spaces.

30. Methodology
⚫ IHC is needed to determine L1-CAM, p53, and MMR protein
expression (MLH1, PMS2, MSH2, and MSH6). Pathogenic POLE-
mutations and CTNBB1-exon 3 status are determined by DNA
sequencing.
⚫ In a small subgroup (3%–6%) of cases the tumor will have more
than one classifying feature (combinations of POLE-mutations,
mismatch-repair deficiency, and p53-abnormal staining).
⚫ Risk profiles for these so-called ‘multiple classifiers’ are assigned
as follows:
⚫ favorable in case of a POLE-mutation irrespective of other classifiers
⚫ intermediate if both MMR deficiency and p53 abnormal staining, but
unfavorable if also substantial LVSI or L1-CAM overexpression is
found.
⚫ In any other case the least favorable factor will determine the risk
profile
Dr Shruthi Shivdas

31. PORTEC4a so far…...
⚫ The pilot phase (first 50 patients) of the PORTEC-4a trial
was completed and showed that the trial design is
acceptable for patients and feasible in terms of the
logistics for determining the molecular profile within 2
weeks.
⚫ Estimated dates for completing accrual and presenting
results Estimated date for completing accrual will be late
2021. Estimated date for presentation of (first) results is
expected in 2023.
⚫ 366 patients (n=500) accrued at the time of publication.
Dr Shruthi Shivdas

32. ESMO ESGO ESTRO 2020
Dr Shruthi Shivdas

33. ESMO ESGO ESTRO 2020
⚫ The decision to use molecular classification in all endometrial
carcinoma cases in the subset of high-grade or high-risk tumors or in
none of the cases depends on the availability of resources and decision
by the multi-disciplinary team of each center.
⚫ Molecular classification is recommended to be performed by the TCGA
surrogate using the diagnostic algorithm provided by Vermij et al .
Dr Shruthi Shivdas

34. Low Risk EC
Dr Shruthi Shivdas
2016
2020
NO ADJuvant is
recommended
Omission of
ADJuvant to be
considered (III,A)

35. Intermediate Risk EC
Dr Shruthi Shivdas
2016
2020
Adj BT recommended
Omit <60 yrs
⮚ Adj BT recommended
⮚ Omit <60 yrs
⮚ For p53abn carcinomas restricted to
a polyp or without myometrial
invasion, adjuvant therapy is
generally not recommended (III,C)

36. High Intermediate Risk EC
Dr Shruthi Shivdas
2016
2020
Adj BT
EBRT if sub LVSI / stage 2 / unstaged
CT if high grade / subLVSI

37. High Risk EC
Dr Shruthi Shivdas
2016
2020
EBRT with concurrent and adjuvant chemotherapy
(I, A) or alternatively sequential chemotherapy and
radiotherapy is recommended (I, B).
Chemotherapy alone is an alternative option (I, B).

38. CT vs CTRT
Scheduling CTRT
CT vs CTRT in HR EC
⚫ Although no differences in RFS & OS were found in GOG 258 for CT vs CTRT
(PORTEC3 schedule), significantly more vaginal recurrences (HR 0·36) and pelvic or
para-aortic, or both, recurrences (HR 0·43) were seen in women treated with
chemotherapy alone.
⚫ In retrospective cohorts, a high frequency of locoregional recurrence was also found
after treatment with chemotherapy alone, supporting the continued use of pelvic
radiotherapy in patients undergoing adjuvant chemotherapy.
Schedue of CTRT
⚫ concurrent start of both modalities followed by adjuvant (PORTEC 3 schedule) might
be the most effective and efficient
⚫ This schedule has now been proven safe and effective in two large, randomised trials
(phase 2 RTOG -9708 & PORTEC 3) with toxicity and QOL data, whereas no phase 3
evidence is available for the specific benefit for other sequences of RT + Ct (sequential
CT--🡪Rt / sandwich)
PORTEC 3 post hoc group
Dr Shruthi Shivdas

39. Future Directions….
Dr Shruthi Shivdas

40. NCCN 2021
Recurrent / Metastatic I line
⚫ Trastuzumab – Stage III/IV EC or recurrent Her 2 +
USC
⚫ Pemrolizumab in MMRd (Phase I KEYNOTE – 028)
⚫ Pembrolizumab / Lenvatinib for MMR p
⚫ Evrolimus / Letrozole in endometroid
Dr Shruthi Shivdas
FDA approved Dostarlimab in MMRd advanced / recurrent EC
based on GARNET (phase 1)
500 mg ever 3 weeks x 4--🡪 1000 mg every 6 weeks till progressio /
unacceptable toxocoty.
Not included in NCCN

41. ⚫ to characterize clinical features and mutational profiles
of recurrent, low-grade, non-myoinvasive, ‘ultra-low
risk’EECs
⚫ total of 486 patients with ultra-low risk endometrioid
endometrial cancers were identified: 14 (2.9%) of 486
patients developed a recurrence
⚫ 2.9% of patients, who developed recurrence, had no
identifiable clinical or pathologic risk
⚫ Most recurrent were MSI; TP53 and CTNNB1 exon3
mutation more in recurrent group, but non significant
association.
Dr Shruthi Shivdas
APRIL 2021

42. Dr Shruthi Shivdas

43. Points to note----
⚫ POLE mutations are more frequently found in
⚫ tumors of relatively young women with lower BMI
⚫ higher-grade endometrioid endometrial tumors compared to POLE-wildtype EC.
⚫ favourable prognosis, which possibly, cannot be improved by CT / RT as their radio- or
chemoresponsiveness is not high.
⚫ MSI-positive tumors (20–40% of all EC patients) have an intermediate prognosis
⚫ associated with negative prognostic factors such as higher histologic grade, presence of LVSI, and
with older age and advanced stage (III/IV)
⚫ very responsive to immunotherap and radiotherapy.
⚫ characterized by a high number of TILs
⚫ MSI+ pa tients respond well to radiation and adjuvant radiation is able to improve their prognosis
dramatically in contrast to MSI negative patients
⚫ NSMP subclass contains a heterogeneous set of tumors, which complicates the distinction of
favorable or unfavorable tumors
⚫ Martinz et al. The brave new world of endometrial cancer . Strahlenther Onkol March 2020
⚫ prognostic studies focused on high-risk endometrial carcinoma (also including CCC) have shown that
the CNL subgroup bears a prognosis definitely worse than those of the POLE and MSI sub- groups.
Travaglino et al. CCC and the TCGA . 2019
Dr Shruthi Shivdas

44. PORTEC 4 a
Dr Shruthi Shivdas
HIGHLIGHTS
⚫ PORTEC-4a is the first trial to introduce molecular
factors in the adjuvant treatment of endometrial
cancer.
⚫ Randomization between standard treatment vs
individualized treatment based on the molecular
risk profile.
⚫ PORTEC-4a will show if omitting treatment in cases
of favorable molecular profiles is safe and cost-
effective.