Many Biliary Tract Cancers Harbor Actionable Mutations

Jeffrey S. Ross, MD

Two-thirds of patients with biliary tract tumors may harbor genomic alterations that could potentially be targets in precision medicine, according to a study led by Jeffrey S. Ross, MD, professor and chair of the department of pathology and laboratory medicine at Albany Medical College in New York.

Comprehensive genomic profiling (CGP) could be used to guide the selection of targeted therapies approved in other tumor types, or to adapt novel therapies available in clinical trials, Ross suggested at the 2015 Gastrointestinal Cancers Symposium (Abstract 231).

“Given the limited treatment options and poor prognosis of patients with biliary tract cancers, and the diversity of clinically relevant alterations identified, CGP appears to have significant potential to maximize the identification of new treatment paradigms and meet an unmet clinical need for this devastating disease,” he said.

Biliary tract cancers include 3 tumor types: intrahepatic cholangiocarcinoma (IHCCA), extrahepatic cholangiocarcinoma (EHCCA), and gallbladder carcinoma (GBCA). These tumors typically present at an advanced clinical and pathologic stage, and they are typically refractory to conventional therapies, including cytotoxic chemotherapy and radiation.

“We queried whether comprehensive genomic profiling of these tumors would reveal clinically relevant genomic alterations that could lead to targeted therapies,” Ross said.

Ross and his colleagues extracted DNA from 554 biliary tract cancer specimens (primary or metastatic), upon which they performed hybridization capture, based on next-generation sequencing, of all coding exons of 315 cancer-related genes and 47 introns of 19 genes commonly rearranged in cancer. The aim was to identify clinically relevant genetic alterations linked to drugs on the market or under evaluation in mechanism-driven clinical trials.

They examined 412 cases of IHCCA, 57 cases of EHCCA, and 85 cases of GBCA, sequencing the specimens to high, uniform coverage.

Genomic Distributions Differed by Tumor Type

CPG of IHCCA tumors revealedTP53to be the most commonly altered gene, followed byP16, thenKRAS. For EHCCA,KRASwas the most commonly altered gene, followed byTP53, thenP16. For GBCA,TP53topped the list, and, interestingly, amplification ofERBB2(HER2)was also common.

“We saw differences and similarities among the 3 tumor types. There is a wide diversity in type of alteration, and small numbers of alterations in a few patients that create the landscape of attempted or available targeted therapies,” Ross said.

While the frequency of particular alterations varied among the tumor types, the total number of genomic alterations per patient and the total of clinically relevant, ie, ‘actionable,’ mutations were similar (Table).

Table. Summary of Genomic Alterations in Biliary Tract Cancers

CGP Findings

IHCCA

EHCCA

GBCA

Total genetic

3.6

4.4

4.0

CRGA/patient

2.0

2.1

2.0

ERBB2amplification

4%

11%

16%

BRAFsubstitutions

5%

3%

1%

KRASsubstitutions

22%

42%

11%

PI3KCAsubstitutions

5%

7%

14%

FGFR-1-3fusions and amplifications

0%

7%

3%

CDKN2A/Bloss

27%

17%

19%

IDH1/2substitutions

20%

0%

0%

ARID1Aalterations

18%

12%

13%

METamplification

2%

0%

1%

CRGA, clinically relevant genetic alteration.

ERBB2amplifications occurred in 16% of the GBC patients; “the same as one encounters in breast and upper gastric/esophageal carcinomas…and were extremely low for IHCCA, at only 4%.”

BRAFsubstitutions were most common in IHCCA; all wereV600Emutations “and therefore possibly targetable,” he noted.KRASsubstitutions, on the other hand, while occurring in 42% of EHCCA, were still low for this tumor type, versus pancreatic ductal carcinoma, where the mutation rate is at least 95%, Ross said.

PI3KCAalterations had a similar rate across tumor types and were low in all 3. Fibroblast growth factor receptor(FGFR)amplifications and fusions were essentially limited to the IHCCA tumor type.

“Fibroblast growth factor receptor-2 fusion is becoming a signature marker of the IHCCA tumor type,” according to Ross.

CDKN2A/B (P16)loss was similar across the groups, representing cell cycle dysregulation.IDH1/2alterations were exclusively identified in IHCCA tumors “and represent a diagnostic alteration and potential opportunity for treatment in this tumor type,” he said.

Alterations inARID1A, the chromatin remodeling gene, were similar across the types.METwas amplified rarely, compared with hepatocellular carcinoma, in which alterations are frequent.

Patients Respond to Targeted Therapies

Many of the patients with actionable mutations were then given the opportunity for treatment based on their genetic profile, receiving targeted agents they would probably otherwise never have been given.

One 67-year-old patient with metastatic IHCC and aBRAFmutation was treated for 8 weeks with aBRAFinhibitor. After 16 weeks, positron emission tomography—computed tomography (PET-CT) demonstrated a continued lack of fluorodeoxiglucose (FDG) avidity and a reduction in a large liver metastasis, from 3.7 cm at baseline to 1.3 cm with treatment. A patient with GBCA had a rareFGFR3-TACC3fusion, and after 4 months was stable on dovitinib. A 64-year-old patient with recurrent GBCA had anERBB2amplification and responded to trastuzumab and chemotherapy, with stable disease at 8 months.

When asked whether or not these mutations were associated with outcomes, Ross responded, “Here, we were only searching for therapy targets. We did not have outcome data to put prognostic results into the study at this point, but we are hoping to get follow-up to see if certain mutations are prognostic of outcome.”¹

Ross JS, Wang K, Catenacci DVT, et al. Comprehensive genomic profiling of biliary tract cancers to reveal tumor-specific differences and genomic alterations.J Clin Oncol.