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Unusual challenges in clinical oncology: YO case discussions

YO9 - Primary refractoriness of recurrent ovarian clear cell carcinoma to anti–PD-1 inhibitor-based therapy in a patient with Lynch syndrome: Never take for granted


03 Dec 2022


Unusual challenges in clinical oncology: YO case discussions


Genetic and Genomic Testing;  Immunotherapy

Tumour Site

Ovarian Cancer


Jack Chan


J.J. Chan

Author affiliations

  • Department Of Breast & Gynaecology, Division Of Medical Oncology, National Cancer Centre Singapore, 169610 - Singapore/SG


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Abstract YO9

Case summary

Mdm N was a 50-year-old Chinese female with a family history of Lynch syndrome (LS)-related cancers. She was initially diagnosed with FIGO stage IIIC right ovarian clear cell carcinoma in Jan 2020. Her cancer responded partially after 3 cycles of neoadjuvant Paclitaxel/Carboplatin, and Mdm N underwent interval debulking surgery in Apr 2020. She further received 3 adjuvant cycles of platinum-based chemotherapy. Germline multi-gene panel testing revealed a pathogenic variant in MSH6 c.642del (p.Tyr214*). After a platinum treatment-free interval of 5 months, her ovarian clear cell carcinoma relapsed in Nov 2020, presenting with ascites, and involving her liver, peritoneum, lungs, and lymph nodes. Based on assumed secondary platinum resistance, Mdm N received second-line Pembrolizumab/Bevacizumab for 2 cycles but her cancer progressed. Post-progression biopsy of a liver metastasis was performed. Unexpectedly, tumour profiling showed intact mismatch repair (MMR) proteins by immunohistochemistry, and microsatellite stable as assessed by next generation sequencing (NGS). Furthermore, on NGS, the MSH6 pathogenic variant identical to the germline finding was identified at a variant allele frequency of 46.1%, together with amplification of EGFR and ZNF217 genes, plus ARID1A G81fs*30 and Q944*. Tumour mutation burden was 5 mutations per megabase. Third-line liposomal Doxorubicin/Bevacizumab was complicated by grade 4 submassive pulmonary embolism and grade 3 hypercalcaemia. Mdm N succumbed to her cancer within 5 months of its metastatic relapse. This case demonstrates that proficient MMR tumours can arise in individuals with LS, thereby accounting for primary refractoriness to a therapeutic strategy based upon immune checkpoint inhibition.

Clinical trial identification

Editorial acknowledgement

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