BRCAness Phenotype May Predict Intraphepatic Cholangiocarcinoma Response To Treatment

Author: Lynda Williams, Senior medwireNews Reporter

medwireNews: Patients with advanced biliary tract cancer (BTC) who have at least one BRCAness mutation have a better response to platinum-based chemotherapy than those without, say Italian investigators. 

The research was reported at the ESMO World Congress on Gastrointestinal Cancer 2022 in Barcelona, Spain, and published in the European Journal of Cancer. 

Presenting author Margherita Rimini, from San Raffaele Hospital in Milan, explained to medwireNews that as there is “no global consensus about the definition of BRCAness in BTC”, the team modified the BRCAness definition for pancreatic cancer, adding extra DNA damage repair (DDR) gene mutations that have been identified in BTC, such as ARID1A. 

Of the 150 patients who received palliative chemotherapy for unresectable, metastatic or recurrent intrahepatic cholangiocarcinoma, 72 patients carried one or more mutations in 23 BRCAness genes, namely ATM, BAP1, BARD1, BLM, BRCA1, BRCA2, BRIP1, CHEK2, FAM175A, FANCA, FANCC, NBN, PALB2, RAD50, RAD51, RAD51C, RTEL1, ARID1A, ATR, ATRX, CHEK1, RAD51L1 and RAD51L3. 

Among these individuals, the most common mutations in BRCAness or other genes were ARID1A (44%), CDKN2A (32%), KRAS/NRAS (22%), CDKN2B (18%), BRCA2 (18%), PBRM1 (17%), ATM (15%), FGFR2 (14%) and TP53 (11%). 

The only significant difference between the BRCAness phenotype and wild-type patient groups in non-BRCAness genetic mutations was for a mutation in CREBBP (10 vs 0%). 

Patients with a BRCAness mutation had significantly longer progression-free survival (PFS) than those without, at a median 7.3 versus 5.4 months and a hazard ratio (HR) of 0.68. There was also a significant improvement in the disease control rate for patients with versus without a BRCAness mutation (77.8 vs 67.9%) and a trend towards better median overall survival (OS), although this did not reach statistical significance (25.4 vs 16.7 months; HR=0.77). 

After adjustment for ECOG performance status and diagnosis of locally advanced versus metastatic disease, BRCAness phenotype remained a significant predictor for better PFS (HR=0.66) and continued to show a trend towards better OS (HR=0.84), the researchers say. 

Margherita Rimini therefore suggested that the BRCAness phenotype might now be “taken into consideration in the daily decision making process”. 

The presenter also reported that three patients with locally advanced disease received a PARP inhibitor after chemotherapy; one patient with a somatic BRCA2 mutation, one patient with an ATM mutation and a third with a PALB2 mutation. These patients achieved OS durations from start of PARP inhibition of 2.4, 11.4 and 4.0 months, respectively. 

Margherita Rimini highlighted the “double trend” of the OS curves, initially favouring patients with BRCAness mutations but on progression favouring those with a wild-type phenotype. The authors believe this might indicate that patients with a BRCAness mutation who benefit from platinum chemotherapy could “freeze” their response with maintenance treatment. 

“[I]n the future, clinical trials investigating the role of PARP inhibitors as maintenance therapy after response to platinum-based chemotherapy in BTC might be conducted in order to verify this hypothesis”, Margherita Rimini commented. 

The investigator also said that research into germline DDR mutations is now beginning and that consideration of “variants of uncertain significance” and loss of heterozygosity will help to “deepen the definition of BRCAness phenotype.” 

Reference  

Rimini M, Marcarulla T, Burgio V, et al. Gene mutational profile of BRCAness and clinical implication in predicting response to platinum-based chemotherapy in patients with intrahepatic cholangiocarcinoma. Ann Oncol 2022; 33 (suppl 4): S357. doi: 10.1016/j.annonc.2022.04.402