CG Consult of the week 27.09.2023

Case History:

  • 51-year-old male presented with abdominal pain
  • no prior history of hepatitis B or C infection or any other illnesses.
  • PET-CT revealed a liver lesion with enlarged hilar lymph nodes, biopsy diagnosed as cholangiocarcinoma
  • Patient received 5 cycles of FOLFOX6 regimen with minimal tumour response, and underwent surgical resection followed by systemic chemotherapy 
  • Upon signs of possible disease progression, CT scan confirmed radiological progression 
  • Postoperative biopsy was sent for clinically validated molecular profiling

Genomic Profiling Results:

  •   BRCA2 S1741fs*36
  • ARID1A Q501*
  • CDKN2A/B loss
  • TP53 H193R

Additional Biomarker Results:

  • PD-L1 expression (IHC): 0% positive for combined positive score (CPS)

Questions from the oncologist:

  • What does the BRCA2 mutation imply for my treatment strategy?
  • Is this a homologous repair deficient (HRD) tumour?


First, advise the oncologist that patient support and advocacy groups exist for patients with cholangiocarcinoma at and the

Germline or somatic BRCA mutations are increasingly described in biliary tract cancer (BTC)(1) and these mutations, like in other tumor types, have been shown to result in defective homologous recombination repair (HRR) mechanisms for double-strand DNA breaks(2).  Hence, BRCA1/2 mutated cancers have been associated with increased sensitivity to DNA-damaging therapies including platinum chemotherapies. This patient did not respond to platinum chemotherapy, so we next consider Poly(ADP-ribose)polymerase (PARP) inhibitors. There are single case reports of the efficacy of PARP inhibitors in patients with BRCA-mutated advanced BTC (3-5) with overall survival ranging from 11 to 65 months; could this patient benefit from PARP inhibitors? Although the BRCA2 frameshift mutation seen in this tumor is expected to result in a disrupted protein product, there is no functional evidence for this BRCA2 variant. A recent study demonstrated that allelic status of alterations in strong HRR genes (BRCA1/2, PALB2, RAD51C/D) can help distinguish loss-of-function from biologically neutral alterations(6). It was reported that biallelic, but not monoallelic, alterations in BRCA1/2 were associated strongly with elevated loss of heterozygosity which is a phenotype for underlying deficiency in HRR (otherwise known as homologous recombination deficiency or HRD), representing a therapeutic vulnerability targetable by PARPi(6).
The BRCA2 alteration in this case was found to be monoallelic, which may explain the lack of response to platinum chemotherapy and potentially preclude benefit from PARP inhibitors.

Learnings from this case:

  • Both the presence and allelic status of alts in strong HRR genes need to be interrogated to better identify cancers with profound defects in HRR.
  • Distinguishing monoallelic from biallelic status is critical in refining HRR alteration as a predictive biomarker for PARP inhibitors.




Disclaimer: all CGCotW cases are based on a true story. No resemblance to persons alive or deceased is intended or should be inferred. ©️ CGC Genomics Consults AG

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