BRCAness May Predict Response to Platinum-Based Chemotherapy in Intrahepatic Cholangiocarcinoma

Margherita Rimini, MD, San Raffaele Hospital, Milan, Italy, reviews the findings from an analysis of tissue specimens from patients with biliary tract cancers treated with platinum-based chemotherapy to identify the presence of BRCAness mutations. The goal of this study was to determine if there was any association between BRCAness mutations and response to platinum-based chemotherapy and PARP inhibitors.

These findings were presented at the 2022 ESMO World Congress on Gastrointestinal Cancer in Barcelona, Spain.

Transcript:

Hi to everyone, I am Margherita Rimini from San Raffaele Hospital of Milan, and I will review my presentation from the 2022 ESMO World Congress on Gastrointestinal Cancer, about the gene mutational profile of BRCAness and its clinical implication in predicting response to platinum-based chemotherapy in patients with intrahepatic cholangiocarcinoma.

We know that the concept of BRCAness has been proposed to indicate the phenotype which some sporadic tumors share with [certain] cancers, and that's concerning not only BRCA1 and 2 mutations, but also genes involved in [DNA damage response and repair] DDR.

We know that the presence of the BRCA1 and 2 mutations could confer a susceptibility to platinum-based chemotherapy in several cancers, but the data about the [biliary tract cancers] BTC are low and poor. For this reason, we performed a retrospective study on 150 patients with locally advanced or metastatic cholangiocarcinoma treated with platinum-based chemotherapy. For each of these tumors, we performed a genomic profiling, by definition, 1 assay. The primary objective was to study the associations between the BRCAness genotype with survival outcomes, whereas the second objective was to perform a comparative study from the genomic point of view.

We included in the study 150 patients, of which 72 were BRCAness, 48% of the sample, and 78 were BRCAness wild-type. The 2 groups of patients were almost homogenous except for the proportion of male versus female, and for the number of patients affected. From the genomic point of view, the most commonly altered genes we saw were CDKN2A, ARID1A, CDKN2B, KRAS/NRAS, BAP1, PBRM1, and TP53. Despite this, there was a different distribution between the BRCAness wild-type and the BRCAness patients concerning the gene mutations. After excluding all genes included in the BRCAness definition, there were no significant differences between these 2 groups of patients.

I would like to specify that the definition of the BRCAness, in BTC, almost does not exist now, so we decided to translate this definition from the advanced pancreatic. At the univariate analysis, the BRCAness, the phenotype, was associated with a longer progression-free survival [PFS], with a reduction of the risk of progression of 32%. Concerning the [overall survival] (OS), a trend toward a benefit in survival was seen with a median OS for BRCAness patients of 25.4 months, compared to 16.7 months in wild-type, without reaching statistical significance. Concerning the disease control rate, BRCAness patients experienced a better disease control rate of 78%, compared to 68% for BRCAness wild-type patients.

Following the adjustment for clinical covariances which are known to prognostic in this setting, including [Eastern Cooperative Oncology Group] ECOG performance status as well as stage of the disease, we see that the presence of a BRCAness phenotype was associated with an improved PFS in patients treated with platinum-based chemotherapy. Concerning the survival curves, we can see that these curves showed 2 trends, which are different, because in the first part, the 2 curves split up in favor of BRCAness patients, but after a progression to platinum-based chemotherapy, these 2 curves experienced a kind of cross. It seems like that the BRCAness patients would benefit more from platinum-based chemotherapy, but when they see maximum benefit has been achieved, a treatment able to freeze these responses could be considered.

In other words, I think that our study opened the question of whether, even in BTC, BRCAness seen in patients would see a benefit from a maintenance treatment with inhibitors of PARP, like olaparib. For this reason, we show the survival outcomes of 3 BRCAness patients that were included in the sample and treated with olaparib after response to platinum-based chemotherapy. Unfortunately, 2 of these patients had to stop treatment early due to adverse events, but 1 patient, who was carrying an [ataxia telangiectasia] ATM mutation, experienced an interesting PFS, and an interesting OS under the olaparib.

In conclusion, I think that it's interesting result, because it's one of the first pieces of evidence of the benefit, in terms of PFS, in a BTC setting, and I think that it's interesting to notice this kind of cross of the survival curves, which seems to suggest a potential to see benefit with an inhibitor of PARP, like the maintenance treatment after a response to platinum-based chemotherapy.

Source:

Rimini M, Macarulla 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. Presented at: ESMO World Congress on Gastrointestinal Cancer; June 29-July 2, 2022. Barcelona, Spain. Abstract SO-3.