Effectiveness of Olaparib Treatment in a Patient with Gallbladder Cancer with an ATM‐Inactivating Mutation

Abstract

Introduction

Gallbladder carcinoma (GBC) is a type of biliary tract cancer with a poor prognosis and a high fatality rate. It is commonly diagnosed at an advanced stage and the 5‐year survival is less than 5% [1]. Significant risk factors for GBC development include presence of gallstones, chronic inflammation, anomalous pancreatobiliary ductal junctions, advancing age, and female gender [2]. The best treatment option for patients with GBC is operative resection; however, only 10% of patients are candidates for surgery at initial presentation, and the recurrence rates following surgery are high [3]. For individuals with advanced GBC, the standard first‐line systemic therapy is gemcitabine or 5‐fluorouracil–based chemotherapy, and the median overall survival was less than 1 year (11.7 vs. 8.1 months; hazard ratio, 0.64; p < .001). At the 2019 American Society of Clinical Oncology Annual Meeting, the results of a phase III trial (ABC‐06) were presented. They revealed that second‐line oxaliplatin plus 5‐fluorouracil chemotherapy (mFOLFOX) was beneficial for patients who had previously been treated, provided a clinically meaningful reduction in risk of death (hazard ratio, 0.69) and a 15% increase in 6‐month and 12‐month overall survival (OS) rate. The researchers recommended that mFOLFOX chemotherapy should become standard of care for second‐line therapy for patients with advanced GBC. In addition, numerous clinical trials have attempted to test the efficacy of targeted drugs administered as monotherapy or in combination treatments; however, no targeted therapeutic regimen has yet been approved for the treatment of advanced GBC [4, 5]. Therefore, there is an urgent need for effective treatment of advanced GBC.

During the past decade, the application of next‐generation sequencing (NGS) has provided a means of high‐throughput identification of cancer driver genes that may be clinically relevant or actionable for precision medicine [6]. However, GBC remains an understudied cancer type. In 2014, Li et al. [7] published a study that used whole‐exome and targeted gene sequencing of GBC to identify 36.8% (21/57) of patients harboring recurrent mutations in the ErbB signaling pathway (including EGFR, ERBB2, ERBB3, ERBB4, and their downstream genes), which suggested that patients might benefit from targeted therapies [8]. Except for anti‐HER2 treatment, limited gene‐based targeted therapies for patients with GBC have been reported. We present the case of a patient with GBC harboring an ATM‐inactivating mutation who had a progression‐free survival (PFS) of approximately 13 months folowing treatment with olaparib. These results may help establish personalized treatment approaches for patients with GBC with ATM‐inactivating mutations.

Patient Story

A 71‐year‐old man, with a 2‐week history of gallstones, was admitted to a hospital in December 2016. Magnetic resonance imaging (MRI) of the abdomen revealed gallbladder cancer (Fig. 1A). The patient underwent cholecystectomy combined with liver resection (segments 4B and 5) on December 30, 2016. The histology revealed a moderately differentiated adenocarcinoma that had invaded the entire layer of the gallbladder wall and nerves, spread to the liver parenchyma, and metastasized to the extrahepatic lymph nodes (region 13). The patient refused adjuvant therapy owing to personal reasons. In June 2017, the patient was readmitted with a month‐long history of jaundice. He had an elevated cancer antigen 19‐9 (CA19‐9) level, and MRI revealed local recurrence (Figs. 1B and 2). Subsequently, percutaneous transhepatic cholangiodrainage was used to relieve jaundice. However, considering his wishes and poor physical condition (performance status 3), systemic chemotherapy was not administered.

Figure 1.

Magnetic resonance imaging scan images of the abdomen (lesions of interest circled red). (A): Baseline (before surgery) images (December 28, 2016). (B): Recurrence after operation. The intra‐ and extrahepatic lesions, jaundice, and lymph node metastasis before initiating olaparib and before initiating olaparib treatment (June 12, 2017). (C): Three months after olaparib treatment (November 6, 2017). The abnormal signal of subcapsular in the operation area was dwindled than before. (D): Four months after olaparib treatment (December 20, 2017). (E): Seven months after olaparib treatment (March 9, 2018). (F): Nine months after olaparib treatment (May 31, 2018).

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Figure 2.

Serum tumor markers after operation and olaparib treatment. Abbreviations: CA‐199, cancer antigen 19‐9; GBC, of gallbladder carcinoma; PTCD, percutaneous transhepatic cholangiodrainage; PD, progressive disease.

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Molecular Tumor Board

After obtaining consent from the patient, the surgically resected tissues were used for testing YuanSu 450 tumor‐related genes. The testing was carried out by OrigiMed, a College of American Pathologists‐accredited and Clinical Laboratory Improvement Amendments‐certified laboratory in Shanghai, China [9]. The results of the tests are presented in Table 1. NGS revealed that the tumor harbored two inactivating mutations, ATM S1905Ifs*25 and STK11 K262Sfs*25, suggesting that the patient might benefit from targeted therapy.

Genotyping Results and Interpretation of the Molecular Results

Ataxia‐telangiectasia‐mutated (ATM) protein, which belongs to the family of homologous recombination (HR), plays an essential role in cellular DNA damage response. When the HR pathway is working properly, DNA can be repaired effectively and is error free, maintaining genomic stability. A deficient HR pathway leads to genomic instability or homologous recombination deficiency (HRD). The most common causes of HRD are germline and somatic BRCA mutations, whereas several other genetic lesions such as ATM, CHEK2, and RAD51 mutations also cause HRD [10]. Patients with HRD are considerably more likely to respond to drugs that impact DNA stability including platinum drugs and poly (ADP‐ribose) polymerase (PARP) inhibitors [11]. The ATM functions in DNA damage repair pathway are shown in Figure 3 [12, 13]. Olaparib, the PARP inhibitor (PARPi), received breakthrough therapy designation by the U.S. Food and Drug Administration (FDA) for treatment of BRCA1/2 or ATM gene‐mutated metastatic castration‐resistant prostate cancer due to the synthetic lethality effect [14]. In addition, a phase II trial (study 39; NCT01063517) of individuals with advanced gastric cancer who had progressed while they were on first‐line therapy revealed that olaparib plus paclitaxel significantly improved OS compared with a placebo plus paclitaxel in participants overall (median OS, 13.1 months in the olaparib group vs. 8.3 months in the placebo group; hazard ratio, 0.56; p = .005) and in participants with low or undetectable ATM protein levels (median OS not reached vs. 8.2 months; hazard ratio, 0.35; p = .002) [15]. However, in subsequent phase III trial, the OS did not differ significantly between the olaparib plus paclitaxel treatment group and the placebo plus paclitaxel treatment group [16], in the participants overall or the ATM‐negative participants. Importantly, ATM‐negative participants were identified through ATM immunohistochemical assays of formalin‐fixed protein‐embedded tissue and not by NGS. Furthermore, deleterious ATM mutations are more often seen in hepatobiliary tumors. Data from The Cancer Genome Atlas (2018) have shown that the frequency of ATM gene mutations in GBC is approximately 6.25% in GBCs. Compared with the United States, the frequency of ATM in the Chinese population is significantly higher (8.3% vs. 1.9%, p = .03%) [17]. Therefore, the evidence of efficacy of olaparib for treating individuals with ATM‐inactivation is more adequate.

Figure 3.

ATM functions in DNA damage repair pathway. Specific types of DNA damage result in the activation of specific DNA repair signaling pathway. Single‐strand break (SSB) is mainly repaired by the base excision repair (BER) pathway, which needs PARP that recognizes and binds to sites of SSB. Then, PARP catalyzes poly(ADP) ribosylation of itself and recruit DNA repair proteins such as DNA polymerase β (POLB), DNA ligase III, and scaffolding proteins such as X‐ray cross‐complementing protein 1 (XRCC1). In the case of double‐strand break (DSB), homologous recombination (HR) plays a crucial role. The H2AX and MRN complex recognize the DSB and recruits ATM and ATR, which can eventually induce cell cycle arrest through p53. Subsequently, ATM can cause the recruitment of BRCA1/2 and PALB2, which determine the RAD51 loading and the subsequent DNA synthesis. In addition, PARP plays a role in activating ATM necessary for HR. When PARP action is inhibited by the PARPi, SSB is converted to DSB at replication. In cells with functional HR pathway, the DSB will be repaired. In cells with a dysfunctional HR pathway, as is the case with BRCA1/2 and ATM, the lesions go unrepaired and cell death ensues.

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Serine/threonine kinase 11 (STK11), also known as liver kinase B1, is the key upstream activator of the AMP‐activated protein kinase (AMPK) pathway [18]. STK11 is frequently inactivated in tumors of the cervix, ovaries, skin, pancreas, and kidneys [19]. STK11‐inactivating mutations are common in individuals with non‐small cell lung cancer through the loss of heterozygosity on chromosome 19p, resulting from non‐sense and missense mutations as well as deletions [20]. Immunohistochemistry revealed the loss of STK11 expression in one of the 38 (2.6%) individuals with biliary cancers [21]. STK11 negatively regulates mammalian target of rapamycin complex 1 (mTORC1; also known as mechanistic target of rapamycin complex 1) kinase activity through AMPK phosphorylation of TSC2 and Raptor; therefore, STK11 inactivation results in mTORC1 hyperactivation [22]. As a result, mTOR inhibition has been extensively tested as a therapeutic approach to targeting STK11‐mutated tumors. There is some evidence that everolimus may be effective for the treatment of individuals with the STK11 mutation. One example is the case of a woman with an adrenocorticotropic hormone‐secreting pituitary carcinoma harboring F298L mutation of STK11. Administering a combination therapy of radiation and everolimus led to clinical improvement and stability on MRI and positron emission tomography for over 6 months in this patient [23]. Another example is the case of an individual with pancreatic cancer with the STK11 D194E mutation, who had a partial response to treatment with everolimus [24].

These reports suggest that anti‐ATM treatment should be a higher priority than everolimus treatment. Considering the wishes and poor physical condition of our patient, and the evidence we described, anti‐ATM treatment was chosen as first‐line treatment.

Patient Update

Oral administration of olaparib (400 mg twice daily) was initiated on July 24, 2017. One month later, the patient's CA19‐9 levels were significantly decreased, as was the abnormal signal in the subcapsular region (Fig. 1C). Most importantly, he was relieved of clinical symptoms. The tumor remained stable until August 2018. After his disease progressed, he underwent liquid biopsy–based circulating tumor DNA testing. The results (Table 1) indicated that ATM S1905Ifs*25 and STK11 K262Sfs*25, which were found in olaparib treatment‐free tissue, were still present, and none of other genes were found to be mutated. The patient began taking oral everolimus 10 mg daily but this did not control the disease. He later died from widely metastatic disease.

The patient was in poor physical condition and unable to receive systemic chemotherapy. NGS detection suggested that he harbored with an ATM‐inactivating mutation. He was treated with olaparib based on the medical evidence and obtained a 13‐month PFS. The medication was well tolerated, with no adverse events. This case suggests that NGS detection could be useful for such patients with no better treatment options and that olaparib might be a drug of choice for patients with advanced GCB with ATM‐inactivating mutations. The clinical significance of the other mutations in the present case remains unclear.

Glossary of Genomic Terms and Nomenclature

Inactivating mutation, also called loss‐of‐function mutation, results in the gene product having less or no function (being partially or wholly inactivated).

Frequent inactivating mutations in suppressor gene have been identified in a wide variety of cancers.

Author Contributions

Conception/design: Wei Zhang, Junping Shi

Provision of study material or patients: Rentao Li, Zhiqiang Han

Collection and/or assembly of data: Guang‐hao Li, Bo Yang

Data analysis and interpretation: Qiang Yin, Yingying Wang, Ling Li

Manuscript writing: Wei Zhang, Junping Shi

Final approval of manuscript: Wei Zhang, Qiang Li

Acknowledgments

We thank the patient and his family. We thank the staff at Tianjin Medical University Cancer Institute and Hospital. We thank OrigiMed for NGS technical support and scientific comments.

This research was supported by funds as follows. (a) National Natural Science Foundation of China, No. 81572434. (b) Ministry of Science and Technology, National Science and Technology Major Special Project: Prevention and Treatment of Major Infectious Diseases such as AIDS and Viral Hepatitis, 2018ZX10723204‐007‐001. (c) “Young Medical Elites,” Tianjin Health and Health Commission. (d) “Young Innovative Talents,” Tianjin Medical University Cancer Institute and Hospital.

Informed consent was obtained from the patient for publication of their information.

Disclosures

The authors indicated no financial relationships.

References

Author notes