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19 - 20 May, 2022

Into the clinic II

Type II endometrial cancer

• A 61 year old female patient presented with intermittent vaginal bleeding since 8 months.
• Postmenopausal since 6 years
• Medical history: diabetic and hypertensive
• Family history: two 1^st degree relatives of breast cancer diagnosed at their 4^th decades one of them was triple negative.

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• Transvaginal us:
• endometrial soft tissue mass is seen infiltrating the myometrium.

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Question:

• What are the radiological red flag criteria that is seen in the TVUS that make us suspect endometrial cancer?

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Introduction

• Endometrial cancer is the most common malignancy of the female genital tract in developed countries.

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• Prognosis depends on the patient’s age, histological type of malignancy, tumor grade, lymphovascular space invasion, tumor size, depth of myometrial invasion ,cervical stromal invasion and tumor involvement of the lower uterine segment.

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• Tumor size, depth of myometrial invasion and cervical stromal involvement cannot be determined by clinical examination.

Radiological diagnosis

• Different imaging modalities as TV US & MRI being used to improve preoperative evaluation.

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• Transvaginal ultrasonography (US) is the first-line imaging modality for evaluation of the endometrium.

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• Postmenopausal patients who present with vaginal bleeding should undergo transvaginal US.

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Transvaginal US technique

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• TVS scan is done at the lithotomy position, with an empty UB and the pelvis is slightly elevated we comment on:

-The uterus in longitudinal and transverse views

-The cervix and lower uterine segment .

-The echo pattern of the myometrium and we searched for any focal lesion.

*Then we measures the thickness of endometrium in mid sagittal , its regularity, and echo pattern.

*The measurement is of the thickest echogenic area from one basal endometrial interface across the endometrial canal to the other basal surface.

*If there is fluid do not include it in the measurement.

-Then evaluated the ovaries and adnexa,

-Finally we evaluate the cul-de-sac for the presence of free or localized fluid, and whether it was clear or turbid.

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Normal TVS appearance of endometrial in premenopausal women

• The endometrium varies in appearance with age and throughout the stages of menstruation.

-In Premenopausal: the normal endometrial thickness varies through the menstrual cycle (less than 16mm).

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Normal premenopausal endometrium obtained during a- menstruation shows a thin endometrial lining (arrow) with a trace of fluid. b-during the secretory phase of the menstrual cycle shows a thickened, echogenic endometrium c. during the late proliferative phase of the menstrual cycle demonstrates the endometrium with a multilayered appearance

Normal TVS appearance of endometrial in Post menopausal women

• Postmenopausal: >5 mm is thickened (>8 mm if on hormone replacement therapy or tamoxifen) 

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Transvaginal US features of endometrial carcinoma

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• Endometrial carcinoma usually appears as thickening of the endometrium though may appear as a polypoid mass.
• These features are non-specific , as endometrial thickening can also be due to benign proliferation, endometrial hyperplasia , or polyps.
• The US features that are suggestive of endometrial carcinoma rather than hyperplasia include :

-Heterogenicity and irregularity of the thickened endometrial

-polypoid mass lesion

-Irregularity of the endometrium-myometrium-border

-Frank myometrial invasion

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Endometrial hyperplasia

Babbly appearance

Benign polyp

Transvaginal US features of endometrial carcinoma

• Disruption of a subendometrial halo on ultrasound may be suggestive of myometrial involvement.

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66-year-old woman with post-menopausal bleeding. TVUS transverse image showing an endometrial mass with obliteration of subendometrial halo (arrows), reflecting myometrial invasion. Histopathology analysis confirmed the presence of a 5 cm endometrial adenocarcinoma invading 20 mm (> 50%) into the myometrium

TVUS showing a thickened homogenous echogenic endometrium, measuring =2.5 mm with regular borders, preserving subendometrial halo and few variable sized cysts. Histopathology ….endometrial hyperplasia

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TVUS showing a thickened endometrium about =30 mm. It has heterogenous echo pattern with multiple hypoechoic areas & indistinct borders. Histopathology….endometrial carcinoma.

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Thickened endometrial lining with smooth outline:�Serous adenocarcinoma in situ

polypoid mass lesion�Hyperechoic masses are always endometrial in origin�

�Endometroid adenocarcinoma �Loss of margin �

Endometroid carcinoma � large mass with margin loss & disturbed anatomy

• D&C:
• Endometrial high grade papillary serous carcinoma.
• IHC:
• P53: diffuse strong positive.
• ER, WT1 and vimentin : focal positive .
• PR: Negative
• The possibility of ovarian papillary serous carcinoma will be excluded after evaluation of excision specimen in combination with operative & radiologic findings.

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Questions:

• Pathologically how can 1ry endometrial serous carcinoma be differentiated from 1ry ovarian serous carcinoma?

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By Histopathology

• At several times it may not be clear if a serous carcinoma involving the endometrium is primary or metastatic from the ovary.

But we suspect that the uterus is the primary site, even when invasion cannot be demonstrated in the hysterectomy specimen if the ovarian involvement is typically bilateral and characterized by small foci of tumor on the ovarian surface or nodules of tumor in the parenchyma with clusters of tumor cells in hilar vascular spaces

By Immunohistochistry

WT-1 may be focally positive in 20–30% of cases of Endometrial serous carcinoma. If strong and diffuse nuclear expression is observed, Extrauterine serous carcinoma enter the differential (ovarian, tubal, and primary peritoneal examples)

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Question:�

Regarding the TCGA molecular classification how do you apply it now in the daily practice putting in consideration that POLE is still not available in Egypt?

Dualistic classification of endometrial carcinoma

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• According to the classical dualistic model introduced by Bokhman in 1983, endometrial cancer (EC) is divided into two basic types: Type I and Type II, based on clinical and histopathological features

(Jan V Bokhman, Gynecol Oncol , 1983)

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• EC in terms of histopathological characteristics is divided into subtypes: serous carcinoma, clear-cell carcinoma, endometrioid adenocarcinoma and carcinosarcoma. Based on this model, type I tumours are usually low-grade endometrioid, whereas type II are usually high-grade or serous

��Dualistic classification of endometrial carcinoma

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• Molecular evidence shows discrete features of the two EC types in terms of gene copy numbers.
• Endometrioid carcinomas are characterized by mutations in PTEN, KRAS, CTNNB1, PIK3CA and microsatellite instability (MSI)
• On the contrary, non-endometrioid carcinomas (type II) are characterized by different molecular abnormalities showing distinct changes, such as HER2 amplification and TP53 mutations

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 Soslow & Bissonnette, Am J Surg Pathol. 2007

Lax, Virchows Arch. 2004

Kandoth & Schultz, Nature. 2013

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Inconsistency in classical Bokhman's classification

• Bokhman's conception seems to be oversimplified, introducing two homogenous types of EC. Clinical, epidemiological, and molecular evidence suggests that dividing EC into just two types does not reflect the true nature of the endometrial malignant pathology
• There is a subtype of tumours that share mutual features of endometrioid and serous cancers.
• Furthermore, original Bokhman's classification did not include clear-cell carcinoma. Such neoplasms as carcinosarcomas or other undifferentiated carcinomas are omitted in the classification
• Low-grade endometrioid and serous carcinomas reflect distant extremes in regard to clinical and molecular characteristics (“pure” type I or II of EC). However, high-grade carcinomas may be an overlap between the two types, presenting many mutual features that are characteristic of both groups of cancer

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• Although these slides belong to three different cases, with morphologically different pathological subtypes. However they all behaved the same with an clinical presentation at an early stage (stage I), no LVSI, Myometrial infiltration <50%, no LN metastasis or extra-uterine extension.

The Cancer Genome Atlas

• The Cancer Genome Atlas (TCGA), a landmark cancer genomics program, molecularly characterized over 20,000 primary cancer and matched normal samples spanning 33 cancer types
• The Cancer Genome Atlas (TCGA), performed an integrated genomic, transcriptomic and proteomic characterization of 373 endometrial carcinomas using array- and sequencing-based technologies.

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TCGA classification of endometrial carcinoma

1. Ultra-mutated POLE-mutated endometrial carcinoma
2. MisMatch Repair-deficient (MMRd), MSI-high endometrial carcinoma
3. Copy number high analogous subgroup
4. Copy number low subgroup

1. Ultra-mutated POLE-mutated endometrial carcinoma

• Mutations in the exonuclease domain of the DNA polymerase epsilon (POLE), a gene invovled in the nuclear DNA replication and repair
• The exonuclease domain is responsible for proofreading function affected by mutation leading to replication errors
• These tumors has an extraordinarily high somatic mutation frequencies, exceeding 100 mutations per megabase in the majority of cases
• Diagnostic tests: 1- Sanger sequencing 2- next generation sequencing (NGS) with a panel incorporating POLE exons 9-14

1. Ultra-mutated POLE-mutated endometrial carcinoma

• These three cases although they belong to different histopathological subtypes, they belong to the same molecular type (POLE mutated EC)

2. MisMatch Repair-deficient (MMRd), Microsatellite instability-high (MSI-h)

• Dysfunctional mismatch repair (MMRd) proteins MLH1, PMS2, MSH2 and MSH6
• These abnormal proteins develop due to either:
• Somatic mutation in the MMR genes
• Germline mutations in the MMR genes, the later being diagnosed as LYNCH syndrome

LYNCH syndrome is an autosomal dominant cancer susceptibility disorder associated with markedly increased risk of colorectal carcinoma and endometrial carcinoma

3. Epigenetic silencing of MLH1 (promotor hypermethylation)
1. This leads to a high mutation frequencies, usually exceeding 10 mutations per MB

2. MisMatch Repair-deficient (MMRd), Microsatellite instability-high (MSI-h)

• Microsatellites are stretches of DNA with a repetitive sequence of nucleotides which makes them susceptible to acquire errors when the MMR gene is impaired

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2. MisMatch Repair-deficient (MMRd), Microsatellite instability-high (MSI-h)

• If microsatellite testing showed mutations in 30% or more microsatellites is called microsatellite instability-high
• Defects in DNA mismatch repair proteins and subsequent microsatellite instability-high lead to the accumulation of mutation loads in cancer-related genes and the generation of neoantigens, which stimulate the anti-tumor immune response of the host

3. Copy number high analogous subgroup

• Copy number alterations (CNAs) are somatic changes to chromosome structure that result in gain or loss in copies of sections of DNA
• Mutations in the cell cycle master regulator TP53, which has crucial roles in many other cellular processes including apoptosis and DNA damage repair, are observed (92%)
• TCGA reclassified 25% of high-grade endometroid tumors into uterine serous cancers owing to p53 mutations and extensive somatic copy-number alterations
• Somatic copy number alteration burden and TP53 status drive radio-resistance in endometrial cancer

(Vargas & Pretty et al., Gynecol Oncol , 2020)

4. Copy number low subgroup

• EC which lack POLE and TP53 mutations and are microsatellite stable (MSS)
• There is no specific molecular profile and no surrogate marker profile
• This group is diagnosed by exclusion of the other types with a specific profile.

Other classifications: ProMisE

• TCGA classification is based on whole genome sequencing, which is not practical to employ in a clinical setting due to cost and time considerations.
• Therefore, a simple, inexpensive and clinically useable system has been developed by two groups in Vancouver & Netherlands, termed ProMisE (Proactive Molecular Risk Classifier for Endometrial Cancer)
• This classification system uses three immunohistochemical (IHC) stains; p53, MMR proteins PMS2 & MSH6, and POLE exonuclease domain hotspot sequencing – as surrogate markers of the TCGA molecular subtypes

• Tp53 is a tumor suppressor gene, mutation of the gene results in stabilization of the resulting protein and its accumulation inside the cells. However, the protein is inactive
• Areas of P53 wild type (normal) IHC expression which appeared scattered nuclear staining and areas with aberrant (mutational) expression of p53 which appeared as 80% strong and diffuse nuclear staining or complete absence of nuclear staining in all cells or moderate to strong cytoplasmic staining

Other classifications: ProMisE

��Other classifications: ProMisE

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• The resultant molecular subtypes are termed
1. MMR defective (MMR-D, surrogate of MSI-H)
2. POLE exonuclease domain mutant (POLE EDM, surrogate of POLE-mutated group)
3. p53 abnormal (p53abn for staining patterns consistent with missense or null mutations, surrogate of CN high)
4. p53 wild type/nonspecific molecular profile (p53wt/NSMP, surrogate of TCGA CN low)
• The classifier is effective regardless of histologic type, which avoids the problems of inter-observer variation in the diagnosis and grading of endometrial cancers, particularly in high-grade tumors (Talhouk et al., Cancer, 2017)

Other classifications: ProMisE

• Survival analyses demonstrate that the simplified ProMisE molecular subgroups survival features mirror the TCGA genomic classification system.

 Post contrast MRI abdomen and pelvis:

�- Endometrial enhancing soft tissue mass (4x5x4.8 cm) is seen infiltrating the myometrium ( > 50 %) reaching the serosa.

- It is seen infiltrating the left parametrium and the cervical stroma.�

- Retroperitoneal lymphadenopathy the largest (1.9x1.8x2.9cm) ... Suspicious.�

- Bilateral external iliac small lymphadenopathy.�

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 Post contrast MRI abdomen and pelvis:

�- Endometrial enhancing soft tissue mass (4x5x4.8 cm) is seen infiltrating the myometrium ( > 50 %) reaching the serosa.

- It is seen infiltrating the left parametrium and the cervical stroma.�

- Retroperitoneal lymphadenopathy the largest (1.9x1.8x2.9cm) ... Suspicious.�- Bilateral external iliac small lymphadenopathy.�

Conclusion:

�**Endometrial carcinoma of TIIIC2 classification according to FIGO classification.

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FIGO 2009

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CT chest:

Multiple enlarged mediastinal LNs the largest was the prevascular group measured 16x9mm.

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CA-125: 110

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Question:

• Q: Would you consider neoadjuvant chemotherapy in this patient or upfront surgery?

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Surgery for advanced extrauterine EC

• Surgical goal is to have no measurable residual disease.

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• In stage III and IV endometrial carcinoma (including carcinosarcoma), surgical tumor debulking including enlarged lymph nodes should be considered when complete macroscopic resection is feasible with an acceptable morbidity and quality of life profile, following full pre-operative staging and discussion by a multi-disciplinary team.

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• Preoperative systemic neoadjuvant therapy should be considered.

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• Main core of surgical debulking is: TAH + BSO+/- Pelic and Para Aortic LN (selective, grossly enlarged LN)/ excision of omental deposits

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Extensive extrauterine involvement:

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• Unresectable primary tumor due to local extent of disease :

For locally advance EC(vaginal, UB, Bowel or Parametrial involvement) >>>> EBRT+/ Brachytherapy OR Systemic therapy >>> REVALUATION for possiblity of Surgical debulking. Otherwise: Chemotherapy should be considered after definitive radiotherapy.

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• Distant metastatic disease (Liver mets) >> consider sytemic therapy / EBRT/ Hormonal therapy >>>> +/- Palliative Surgery (TAH+BSO)

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Residual pelvic disease (positive resection margin, vaginal disease, pelvic side wall disease)

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• An individualized approach with either radiotherapy or chemotherapy or a combination of both modalities should be considered by a multi-disciplinary team.

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Our case:

• Received 3 cycles neoadjuvant paclitaxel/carboplatin

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• MRI abdomen and pelvis: stationary

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• CT chest: free

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• CA-125: 16

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• Exploration:
• bulky uterus with tumor extending to the pericervical tissue with dilated ureter and heavy nodal infiltration, but no peritoneal disease

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Post operative pathology:

• Specimen 1: uterus, tubes and ovaries:
• - High grade papillary serous carcinoma involving endometrium, cervix, both ovaries and left tube, focal positive for WT-1 mostly of endometrial origin.
• Specimen (2) left iliac lymphadenectomy:
• - Infiltration 1 out of 10 dissected LNs.
• Specimen (3) right iliac lymphadenectomy:
• - Infiltration 3 out of 15 dissected LNs.
• Specimen (4) paraortic lymphadenectomy:
• - Infiltration 3 out of 10 dissected LNs.
• Specimen (5) omental biopsy:
• - Infiltrated by malignant tumor.
• TNM staging: T3 N2 Mx stage IIIc2 at least.
• FIGO IIIc2 at least.

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Questions:

• With infiltrated but unresected omentum what is the best next step for the patient?

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• What would you consider as adjuvant therapy for this case?

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First: Risk stratification

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Molecular risk stratification

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Don’t forget other prognostic factors

• Grade
• LVI

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Back to our patient

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Which chemo?�Why paclitaxel-Carbo?

46% of non-endometrioid cancers had HRD

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Where did adjuvant chemo-radiation come from?

• PORTEC 3 study

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But our patient has stage III disease, and did adequate pelvic surgery

Will she benefit from pelvic radiation?

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Do we need radiation?

GOG 258 study

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Questions:

• The patient is P53 mutated, suppose that POLE mutation is available and it is POLE mutant as well where would that stratify our patient? would you consider adjuvant?

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• Possibility of maintenance (positive ER?)

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Our patient:

• Received 3 cycles paclitaxel/carboplatin then lost follow up.

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• 6 months later > Pelvic pain

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POST CONTRAST MRI PELVIS:

• Large pelvic soft tissue mass.

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• Anteriorly: it's compressing the urinary bladder and with no separate fat planes.

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• Posteriorly: inseparable from the rectum.
• Multiple bony metastasis at the femoral head and pelvic bone and lumbar vertebra...likely metastatic

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• Malignant iliac LNs

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Question:

• What is the role of surgery in recurrent endometrial carcinoma?

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• Endometrial carcinoma is one of the most common female cancers in developed countries.

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• Disease stage is associated with the risk of disease relapse after radical treatment.

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• Typically, the risk of disease relapse peaks at 3 years from local radical treatment and then diminishes over time, so that late relapses(from year 5 afterward) are extremely infrequent.

• Despite optimal surgical and adjuvant treatment, 7–15% of early stage (I-II) patients present with recurrent disease.

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• The risk of locoregional recurrence is low and strongly related to the presence of risk factors, such as LVSI, tumor grade, or molecular profile.

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• About 50% of the patients with a recurrence have locoregional disease, 25% present with distant recurrence, and the remaining 25% have both.

• Recurrent endometrial cancer can be treated via surgery, radiation therapy, hormonal therapy, or chemotherapy.

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• The treatment modality choice largely depends on the localization of disease, the patient's performance status and previous treatment history, and the tumor’s hormonal receptor status.

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• Historically, radical salvage surgery, namely pelvic exenteration has been the mainstay of surgery for selected women with an isolated central pelvic recurrence of endometrial cancer following prior radiotherapy treatment.

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• The aim of such surgery is complete resection, usually necessitating removal of the rectum and bladder en-bloc with the recurrent tumor.

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• Recently, surgical cytoreduction, akin to that employed in the management of recurrent ovarian cancer, has gained interest as a potential surgical strategy for recurrent endometrial cancer. 

• When used in combination with selected post-surgical systemic therapies, cytoreductive surgery may show equivalent or better survival outcomes without the high burden of post-surgical morbidity associated with pelvic exenteration.

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• Furthermore, cytoreductive surgery is not limited to the pelvis and therefore opens up surgical treatment options for patients previously considered inoperable.

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Baseline and clinical characteristics guiding treatment for recurrent endometrial cancer. Identified baseline and clinical characteristics guiding treatment allocation.

Vaginal recurrence:

• In previously irradiated patients, surgical resection is considered to be the first-line treatment option, followed by adjuvant local radiotherapy(brachytherapy) if indicated.

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• Non-irradiated patients are traditionally salvaged with radiation therapy. However, the tumor size significantly influences the effect of radiotherapy and, therefore, surgical resection may be considered as a viable alternative.

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Parenchymal metastasis:

• It is apparent that surgery should play an increasing role in the management of patients with parenchymal metastases from gynecological cancers to the lungs, brain or liver.

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• Appropriate patient selection is critical, but surprisingly good long-term survival results can be achieved for resection of metastases from all three organs, in conjunction usually with the use of adjuvant radiation, chemotherapy or hormonal therapy.

Questions:

• This family history of breast cancer would you suspect a certain genetic disorder?

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• What molecular tests would you consider in this patient?

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• If there was access to clinical trials where would you assign her?

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The “Modern” Molecular Classification: TCGA Classification

• POLE (ultramutated malignancies):
• Their hallmark are mutations in the exonuclease domain of POLE
• POLE encodes the catalytic subunit of DNA polymerase epsilon which plays a relevant role in DNA repair.
• MSI-High: Tumors that harbor a high rate of mutations resulting from impaired DNA MMR pathway:
• A DNA repair system that corrects errors such as single-base mismatches or short insertions and deletions that spontaneously occur during DNA replications
• The most implicated genes are: MLH1, MSH2, MSH6, PMS2

Cancer Genome Atlas Research Network. Nature. 2013;497:67.

Spectrum

MSI high

CN cluster 4

(232)

(215)

(150)

POLE (ultramutated) (17)

MSI (hypermutated) (65)

Copy-number low (endometrioid) (90)

Copy-number high (serous-like) (60)

Mos

120

0

20

40

60

80

100

100

80

60

40

20

0

PFS (%)

Log-rank P = 0.02�POLE (ultramutated)�MSI (hypermutated)�Copy-number low (endometrioid)�Copy-number high (serous-like)

+

+

+

Integrated Molecular Classification of Endometrial Cancer

CN high: 2-3 mut/Mb, �TP53 mutations, high grade

TCGA. Nature. 2013;22;500:415.

CN low: 2-3 mut/Mb, endometrioid, PTEN and �CTNNB1 mutations, G1

MSI-H group with �10-20 mut/Mb, endometrioid, PTEN mutations, mixed grade

POLE mutations are �ultramutated, �100-500 mut/Mb, endometrioid, PTEN

Ultramutated (POLE)

Hypermutated (MSI/MLH1)

Copy number low

Copy number high

Legend

Histology �Grade

PTEN�TP53

POLE�MSI/MLH1�CNA

Substitution�Frequency (%)

Mutations per Mb

500

50

5

0.5

100

80

60

40

20

0

From Biology To Precision

Current Standard of Care for Advanced/Recurrent Endometrial Cancer

1. Miller. JCO. 2020;38:3841-3850. 2. Fader. Clin Cancer Res. 2020;26:3928.

GOG-3007 Phase II Study: Everolimus + Letrozole vs Tamoxifen + MPA in Recurrent/Persistent Advanced EC

Slomovitz. SGO 2018. Abstr 1. NCT02228681.

PFS by Regimen

PFS Probability (%)

Mo on Study

Everolimus, Letrozole

Tamoxifen and MPA

Events

26

31

Total

37�37

OS by Regimen

OS Probability (%)

Events

13

20

Total

37�37

Tamoxifen and MPA

Everolimus, Letrozole

Mo on Study

Patients with Advanced (stage III/IV) persistent or recurrent measurable Endometrioid EC unlikely cured by surgery or RT (N = 74)

Everolimus 10 mg/day +� Letrozole (n = 37)

Tamoxifen 20 mg + Medroxyprogesterone � (n = 36)

• Primary endpoint: ORR , Secondary endpoints: PFS, OS, safety

KEYNOTE-158: Pembrolizumab for Advanced Endometrial Cancer

100

80

60

40

20

0

-20

-40

-60

-80

-100

20% tumor

increase

30% tumor

reduction

Change From Baseline (%)

*ORR 45.5% in cohort D (n = 11)and 60.5% in Cohort K (n = 38)

O’Malley. Annals of Onc. 2019;30:403. Marabelle. JCO. 2020;38:1.

MSI-H Advanced EC

Patients with unresectable/metastatic endometrial cancer with progression on or intolerance to standard therapy; ECOG PS 0 or 1

Pembrolizumab 200 mg IV Q3W

Up to 35 cycles or until PD

GARNET: Dostarlimab (TSR-042) Monotherapy in Endometrial Cancer

Part 2B Expansion Cohorts

Cohort A1^†: dMMR EC

Dostarlimab 500 mg IV Q3W for 4 cycles, then 1000 mg IV Q6W

(n = 129)

Cohort A2^‡: pMMR EC

Dostarlimab 500 mg IV Q3W for 4 cycles, then 1000 mg IV Q6W

(n = 161)

Dostarlimab

1-20 mg/kg IV on D1, 15 of

28-day cycle

Dostarlimab

500 mg IV Q3W or 1000 mg IV Q6W

on D1 of 21- or 42-day cycle

Oaknin. ESMO 2020. Abstr LBA36. NCT02715284.

Multicenter, open-label, single-arm, phase I study

Adults with recurrent/advanced dMMR/MSI-H* or MMR-proficient/MSS endometrial cancer with ≤ 2 prior lines of treatment for recurrent or advanced disease and progression after platinum doublet therapy; measurable disease via RECIST 1.1; no prior anti–PD-L1 (N = 290)

• Primary endpoint: ORR
• Secondary endpoints: DOR, DCR

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Until PD

Part 1

Part 1

Dose Finding

Part 2A

Part 2A

Fixed-Dose Safety Run-in

GARNET: Primary Endpoint Analysis

• ORR was 44.7% in patients with dMMR EC, and 13.4% in patients with MMRp

*Responses required confirmation at a subsequent scan; SD had to be observed at ≥12 weeks on study to qualify as SD; ^†Includes confirmed CR, PR or SD at ≥12 weeks �

Oaknin. ESMO 2020. Abstr LBA36.

Study 309/KEYNOTE-775: Lenvatinib + Pembrolizumab After Platinum in Advanced EC

• Confirmatory, randomized, open-label phase III study

Makker. SGO 2021. Abstr 11512.

• Primary endpoints: PFS by BICR, OS

• Secondary endpoints: ORR, health-related quality of life, pharmacokinetics, safety
• Key exploratory endpoint: DoR

*2 prior regimens allowed if 1 was in neoadjuvant/adjuvant setting.

FDA Accelerated Approval September 2019

FDA Priority Review May 2021�For patients with endometrial cancer �who are not MSI-H or dMMR

Study 309/KEYNOTE-775: PFS and OS Benefit

Makker. SGO 2021. Abstr 11512.

From Biology to Precision Therapy

Immune Checkpoint inhibitors

Hot tumors

Endocrine therapy

Copy number-�low tumors

Targeted therapy

Copy number-�high tumors

Combination therapy

Cold tumors

Ongoing Trials in Advanced/Recurrent EC

1. Makker. JCO. 2020; 38: 2981. 2. NCT03517449. 3. NCT03884101. 4. NCT03367741. 5. NCT03914612. 6. NCT03603184. 7. NCT03981796.

Reference

• E. EPSTEIN1 , D. FISCHEROVA2, L. VALENTIN etal : Ultrasound characteristics of endometrial cancer as defined by International Endometrial Tumor Analysis (IETA) consensus nomenclature: prospective multicenter study: Ultrasound Obstet Gynecol 2018; 51: 818–828.

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• Nalaboff M. K, Pellerito .S. J & Ben-Levi E:Imaging the Endometrium: Disease and Normal Variants: RadioGraphics 2001; 21:1409–1424

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• Gupta A , Desai A, Bhatt S :Imaging of the Endometrium: Physiologic Changes and Diseases :RadioGraphics 2017; 37:2206–2207
• Maturen K: Uterine malignancy what u need to know. PPT.

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References:

*Abu-Rustum NR, Yashar CM, Bradley K, Campos SM, Chino J, Chon HS, Chu C, Cohn D, Crispens MA, Damast S, Diver E. NCCN Guidelines® Insights: Uterine Neoplasms, Version 3.2021: Featured Updates to the NCCN Guidelines. Journal of the National Comprehensive Cancer Network. 2021 Aug 1;19(8):888-95.

**Daix MC, Gladieff L, Martinez A, Ferron G, Angeles MA. Pocket memo based on the ESGO/ESTRO/ESP guidelines for the management of patients with endometrial carcinoma: definition of prognostic risk groups. International Journal of Gynecologic Cancer. 2021 Oct 13:ijgc-2021.

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Thank you!

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