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Ovarian cancer management in the molecular era

Into the clinic series

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Case

62 years old .
PS : ECOG (0)
Presented with Abd distention , dyspepsia .
After 2 months of medical treatment , U/S showed complex adenxial mass, ascites .

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Further Work up

Ca 125 : more than 1000.
He 4 ?
CA 19.9 ? Cea ?

CT versus MRI versus PET CT ?

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�

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Pet CT of Recurrent ovarian carcinoma

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Upfront surgery

NAC

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Lap assessment :

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NAC

Tissue biopsy .

Cytology

3-4 cycles or 6 cycles

Timing of surgery

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Cytology

Rapid method for provisional diagnosis of neoplastic process but can not specify origin, type and grade of the tumor.
Staging (Ascetic fluid, peritoneum, LN)
CTCs

Definitive diagnosis will need IHC to be done on fixed tissue (cell block material or tissue biopsy)

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Cell block material

Can be informative about type of tumor
IHC can be performed to reach accurate diagnosis and subtyping
Not perfect for molecular assessment

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Tissue biopsy

Provides information about architectural pattern of the tumor
Differentiates between different types of ovarian cancer
Differentiates between borderline and invasive tumors
Allows IHC and molecular testing

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High grade serous carcinoma

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Positive markers:

PAX-8, WT-1, CK7, ER (80%), PR (30%), p53, Calretinin and D2-40

High grade serous carcinoma

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Genetic testing

Blood ?

Tissue sample ?

BRCA 1, 2 , Others ?

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HRD testing

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Approximately half of high grade epithelial ovarian cancers harbor defects in HRR

The genetic alterations in this graph have been experimentally found to be associated with HRD, have been reported to confer HRD but data are evolving, or are enriched in cells with HRP

HRD=homologous recombination deficiency; HRP=homologous recombinaiton proficiency; HRR=homologous recombination repair.

Konstantinopoulos PA, et al. Cancer Discov. 2015;5(11):1137–54.

These defects can be identified using different clinical and molecular biomarkers

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Analysis is performed on DNA isolated from FFPE tumor tissue and assesses two factors to determine HRD status¹

Clinically validated methods to detect HRD in newly diagnosed OC require BRCAm testing and scoring of genomic instability^1,2

Loss of heterozygosity �(LOH)¹

Presence of a single allele³

Telomeric allelic imbalance �(TAI)^1�A discrepancy in the 1:1 allele ratio at the end of the chromosome (telomere)⁴

Large-scale state transitions�(LST)¹

Transition points between regions of abnormal and normal DNA or between two different regions of abnormality⁴

Presence of �BRCA mutation

Score out of 100³

Example: Myriad myChoice^® genomic instability

Testing in newly diagnosed ovarian cancer²

Yes

No

Tumour BRCA mutation¹

Genomic instability¹

BRCAm=BRCA mutation; CDx=companion diagnostic; FFPE=formalin fixed paraffin embedded; HRD=homologous recombination deficiency; OC=ovarian cancer

1. Myriad myChoice HRD Technical Specifications. Available at: https://myriad-web.s3.amazonaws.com/myChoice/downloads/myChoiceHRDTechSpecs.pdf (last accessed September 2020); �2. Ray-Coquard I, et al. N Engl J Med 2019;381:2416–2428; 3. Ryland GL, et al. BMC Med Genom. 2015;8:45; 4. Jenner ZB, et al. Fut Oncol. 2016;12(12):1439–1456

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The genomic stability and BRCAm results define a patient as HRD-positive or HRD-negative in the Myriad myChoice^® CDx test

BRCAm=BRCA mutation; HRD=homologous recombination deficiency.

Myriad myChoice HRD Technical Specifications. Available at: https://myriad-web.s3.amazonaws.com/myChoice/downloads/myChoiceHRDTechSpecs.pdf (accessed March 2020).

BRCAm

Non-BRCAm

Myriad myChoice^® CDx test

Tumor BRCAnalysis^®

Genomic instability (LOH, LST, TAI)

Score <42

HRD-positive:

HRD-negative:

Score ≥42

and/or

and

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Test	Clinical validity to predict PARPi benefit
Test	NCCN^1a	ESMO²	ASCO³	SGO⁵
BRCA mutation	Yes	Yes	Yes	Yes
HRD	Yes May inform ‘magnitude of PARPi benefit’^b	Yes^c To inform ‘magnitude of PARPi benefit’	Yes^d To inform ‘use of olaparib + bevacizumab’⁴in 1L	No mention
Non-BRCA HRR gene mutations	No mention	Insufficient evidence	Yes To inform ‘susceptibility to platinum, PARPi or experimental agents’	No mention
BRCA1/RAD51C promoter methylation	No mention	Insufficient evidence	No mention	No mention
Whole genome sequencing	No mention	Insufficient evidence	No mention	No mention

aNational Comprehensive Cancer Network® (NCCN®) makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way; bMay provide information on the magnitude of benefit of PARPi maintenance after 1L CT in the absence of BRCAm (category 2B: Based upon lower-level evidence, there is NCCN consensus that the intervention is appropriate); cHRD-positive defined by either a deleterious or suspected BRCA mutation, genomic instability or LOH (in 1L maintenance setting however, LOH has no evidence of clinical utility); dHRD-positive defined by either tumour BRCA mutation and/or with a genomic instability score ≥42.

1L=first line; ASCO=American Society of Clinical Oncology; BRCAm=BRCA mutation CT=chemotherapy; ESMO=European Society for Medical Oncology; HRD=homologous recombination deficiency; HRR=homologous recombination repair; NCCN=National Comprehensive Cancer Network; PARP(i)=poly (ADP-ribose) polymerase (inhibitor); SGO=Society of Gynecologic Oncology

1. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Ovarian Cancer including Fallopian Tube Cancer and Primary Peritoneal Cancer V.1.2010. © National Comprehensive Cancer Network, Inc. 2020. All rights reserved. Accessed November 2020. To view the most recent and complete version of the guideline, go online to NCCN.org; 2. Miller RE, et al. Ann Oncol. 2020. 2020;S0923-7534(20):42164-42167; 3. Konstantinopoulos PA, et al. J Clin Oncol. 2020;38(11):1222–1245; �4. Tew WP, et al. J Clin Oncol. 2020;38(30): 3468-3493; 5. SGO Clinical Practice Statement: Genetic Testing For Ovarian Cancer. 2014

International guidelines increasingly recognise the value of HRD testing to inform treatment decisions in ovarian cancer

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ESMO guidelines recommend considering HRD testing to identify newly diagnosed patients most likely to gain benefit from a PARPi

HRD test	Test level of evidence	Clinical validity	Clinical utility
HRD test	Test level of evidence	Clinical validity	1L maintenance	PSR disease
Germline BRCA mutations	I	Good	Good	Good
Tumour BRCA mutations	I	Good	Good	Good
Somatic BRCA mutations	I/II	Good/fair	Good	Good
Non-BRCA HRR gene mutations	II	Marginal	No evidence	Marginal
HR genomic scar assays: GIS LOH	� I II	� Good Good	�Good No evidence	� Good Good

In the newly diagnosed setting it is reasonable to use a validated scar-based HRD test to:

Establish the magnitude of benefit conferred by PARPi use in BRCAwt HGSC
To identify the subgroup of BRCAwt patients who are least likely to benefit from PARPi therapy

There is currently an insufficient quantity of evidence to determine the clinical validity of individual or panels of non-BRCA HRR genes for predicting a PARPi response and further prospectively collected data is required

In the newly diagnosed setting g/sBRCAm testing is routinely recommended to identify HGSC patients who should receive a PARPi

1L=first-line; ESMO=European Society for Medical Oncology; GIS=genomic instability score; g/sBRCAm=germline/somatic BRCA mutation; HGSC=high-grade serous ovarian,

fallopian tube and peritoneal carcinoma; HRD=homologous recombination deficient; HRR=homologous recombination repair; LOH=loss of heterozygosity; PARP(i)=poly (ADP-ribose) polymerase (inhibitor); PSR=platinum-sensitive; wt=wild-type

Miller RE, et al. Ann Oncol. 1469-8041. Special article in press. Published September 28, 2020

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Taxol- Carboplatin.

Beva.

PARPi

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Surveillance protocol ?

Every 3 months /6 months /12 months ?

Clinical / Radiological.

Management of biochemical relapse ?

CT, MRI. versus PET CT

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There is uncertainty about the value of early diagnosis and treatment of recurrent ovarian cancer.

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Relapse

28 months later , she developed peritoneal release , ascites .

Surgery versus medical ttt.

HIPEC ??

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Basel Refky, OCMU

12 June 2021

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Basel Refky, OCMU

12 June 2021

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AGO Criteria

Good performance status.

Ascites less than 500 ml.

Achievement of optimal cytoreduction at first surgery.

Isolated recurrence.

Platinum sensitive.

Basel Refky, OCMU

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Website

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