|Year : 2020 | Volume
| Issue : 1 | Page : 29-33
Germline BRCA2 mutation pancreatic adenocarcinoma
Wen-Chun Chen1, Ming-Huang Chen2
1 Division of Hematology and Oncology, Department of Medicine, Taipei Veterans General Hospital; School of Medicine, National Yang-Ming University, Taipei, Taiwan
2 School of Medicine, National Yang-Ming University; Department of Oncology, Taipei Veterans General Hospital, Taipei, Taiwan
|Date of Submission||28-Jul-2019|
|Date of Decision||05-Sep-2019|
|Date of Acceptance||09-Sep-2019|
|Date of Web Publication||2-Mar-2020|
Dr. Ming-Huang Chen
Department of Oncology, Taipei Veterans General Hospital, No. 201, Sec. 2, Shih-Pai Rd., Taipei 112
Source of Support: None, Conflict of Interest: None
Pancreatic adenocarcinoma is one of the most challenging malignancies. Its surgical resection is regarded as the only potential curative treatment. However, most patients present with advanced stages, associated with very poor prognosis. Germline BRCA1 and BRCA2 (BRCA1/2) mutations account for few advanced pancreatic adenocarcinomas and thus present as disease-specific entities. Cancers harboring BRCA1/2 mutations are relatively more chemosensitive and have exhibited survival benefits with platinum-containing combination treatments. FOLFIRINOX has been evaluated in various trials and is a well-established first-line chemotherapy for metastatic pancreatic cancer in patients with good performance status. Here, we report the case of a patient with germline BRCA2-mutation pancreatic adenocarcinoma who exhibited a good response to modified FOLFIRINOX, achieving an 18-month complete response.
Keywords: BRCA, olaparib, pancreatic cancer
|How to cite this article:|
Chen WC, Chen MH. Germline BRCA2 mutation pancreatic adenocarcinoma. J Cancer Res Pract 2020;7:29-33
| Introduction|| |
Pancreatic cancer is a highly lethal malignant disease. Germline BRCA1 and BRCA2 (BRCA1/2) mutations account for approximately 4%−7% of pancreatic adenocarcinomas, and are considered to be a different disease entity. Clinical studies have suggested that tumors harboring a BRCA mutation are more likely to respond to platinum-containing combination treatments and to have a more favorable prognosis.,,, Herein, we present the case of a patient with germline BRCA2-mutated metastatic pancreatic adenocarcinoma who successfully achieved a complete response with FOLFIRINOX treatment.
| Case Report|| |
A 78-year-old man presented to our Medical Oncology Department in June 2017 with high levels of tumor markers, including carcinoembryonic antigen (8.2 ng/dL) and carbohydrate antigen (CA 19-9; 4818 U/mL), detected during a regular health checkup. He did not report a history of weight loss, loss of appetite, changes in bowel habits, or other specific discomfort, and a physical examination revealed only mild upper abdominal tenderness. His family history included type 2 diabetes mellitus, and his two daughters had breast cancer with BRCA2 mutation.
A positron emission tomography-computed tomography (CT) scan revealed fluorodeoxyglucose-avid focus in the pancreatic tail with at least two focal uptakes in the liver; a pancreatic neoplasm with liver metastasis was suspected. Magnetic resonance imaging (MRI) of his abdomen subsequently revealed a mass lesion measuring 4.2 cm in the pancreatic tail, with several nodular lesions in the liver [Figure 1]a. Based on laboratory examination and radiological findings, a multidisciplinary tumor conference consensus was that it was a resectable pancreatic tail tumor. He subsequently received laparoscopic distal pancreatectomy and splenectomy in June 2017. At the time of surgery, the lesion was well defined and measured 3.5 cm (length) ×2.5 cm (diameter). Pathological findings indicated a moderately to poorly differentiated adenocarcinoma without lymph node metastasis, and the tumor was stage pT3N0M1. However, the postoperative CA 19-9 level was elevated to 6740 U/mL, and liver CT demonstrated multiple liver metastases [Figure 1]b. To actively seek further treatment, the patient was then referred for genetic testing. A specimen from the primary pancreatic tumor and a blood sample were sent for a next-generation sequencing assay (ACT Genomics), which identified a somatic KRAS Gly12Asp mutation along with an effective target drug (sorafenib). Furthermore, the copy number variants of heterozygous deletions over ARID1A and FLCN were revealed. Notably, a germline BRCA2 single nucleotide mutation (c. 809C> G) over exon 10 on chromosome 13, leading to Ser270Ter amino acid change, was detected in both the primary lesion and blood sample [Table 1].
|Figure 1: (a) Abdominal magnetic resonance images revealed a heterogeneous lesion with enhancement at the pancreatic tail along with liver metastasis. (b) Abdominal computed tomography revealed multiple liver metastases 1 month after surgical resection. (c) A 16-month complete response of the liver metastases and primary tumor in follow-up magnetic resonance images. (d) Solitary liver recurrent metastasis was noted in March 2019, 18 months after surgery|
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A reduced dose of a modified FOLFIRINOX regimen (i.e., 120 mg/m2 irinotecan, 85 mg/m2 oxaliplatin, 200 mg/m2 folinic acid, and 2000 mg/m2 5-fluorouracil through continuous intravenous infusion over 40 h) was selected as first-line adjuvant treatment, considering his good performance status 1 and genetic results. He received 12 cycles with prophylactic granulocyte colony-stimulating factor support for 6 months (June 2017−March 2018). In January 2019 (6 months after the diagnosis), a repeat abdomen CT revealed complete regression of the metastatic tumors over his liver without evidence of disease at the primary site [Figure 1]c. He then received maintenance treatment with TS-1 (oral tegafur/gimeracil/oteracil) for 12 months (April 2018−March 2019). This treatment was discontinued when recurrence was noted on follow-up MRI in March 2019 [Figure 1]d, with a 1.8-cm nodule at S4a of the liver with low signal intensity on T1-weighted and high signal intensity on T2-weighted MRI with arterial enhancement and isointensity in the delayed phase, which led to peripheral focal bile duct dilatation and perfusion change. Furthermore, his CA 19-9 level increased synchronously to 968 U/mL. He underwent radiofrequency ablation under the impression of solitary liver metastasis and was again treated with the combination FOLFIRINOX regimen in April 2019. Three months after the liver metastases had been discovered, a repeat MRI scan revealed complete remission, and a reduced CA 19-9 level of 357 U/mL was noted.
| Discussion|| |
BRCA1 and BRAC2 are tumor suppressor genes that protect cells by maintaining chromosomal stabilization and genome integrity, thereby enabling an error-free DNA repair process through the homologous recombination pathway following double-strand DNA breaks. Thousands of types of mutations in these genes have been identified, with some being recognized as pathogenic variants that may lead to malignancy development. Germline BRCA1/ 2 mutations are inherited in an autosomal-dominant fashion and are considered to be susceptibility genes for breast and ovarian cancers.,, The prevalence of BRCA2 mutations in Asian populations varies among countries and studies, ranging from 3.1% to 13.5%. Most Asian studies have reported more frequent mutations in BRCA2 than in BRCA1. According to a cross-sectional study of 68 hospitals with women with hereditary breast and ovarian cancer (HBOC) in Taiwan, among the 272 patients analyzed, the prevalence of BRCA2 pathogenic mutation was 6.8% (16/236). The Korean hereditary breast cancer study included a total 2953 individuals with HBOC and reported a prevalence of BRCA2 pathogenic mutations of 3.1% (90/2953). Another study enrolled 260 individuals with HBOC in Japan, of whom 13.5% (35/260) were BRCA2 positive. In addition, another analysis of 94 individuals with breast and ovarian tumors conducted in Singapore revealed a prevalence rate of BRCA2 mutations of 11.1%.,, Moreover, BRCA1/ 2 mutations represent a major genetic predisposition to pancreatic adenocarcinoma, with a 2- to 6-fold increased risk in such patients. BRCA1/ 2 mutations are estimated to occur in approximately 4%−7% of patients with pancreatic adenocarcinoma., Patients with germline BRCA1/ 2 mutations are more likely to develop cancers at a younger age with a more aggressive disease compared to those without germline BRCA1/ 2 mutations.,,, However, the prognosis varies according to the origin of the cancers. Germline BRCA1/ 2 mutations have been associated with a higher risk of nodal involvement, distant metastasis, and poor survival in prostate cancer. However, the prognosis is equivocal or may even be better in patients with pancreatic and ovarian cancers.,BRCA1/ 2mutation tumors typically present with a later clinical stage, a greater possibility of developing metastatic lesions, and a higher pathological grade. In our patient, we detected a single-nucleotide BRCA2 mutation, BRCA2 c.809C>G over exon 10 on chromosome 13, leading to Ser270Ter amino acid change. This variant allele is predicted to encode a truncated nonfunctional protein product and to be related to a hereditary cancer-predisposing syndrome according to the BRCA exchange. The BRCA exchange is a database that aggregates data consisting of the international evidence-based network for the interpretation of germline mutant alleles consortium expert panel, along with expert clinicians, diagnosticians, researchers, and database providers to advance the understanding of BRCA1 and BRCA2 variations.,
Mutations of BRCA1/ 2 interfere with normal cellular function, leading to not only the onset and progression of cancer but also the impaired ability of tumor cells to repair platinum-induced double-strand breaks. Thus, these tumors may be more chemosensitive to DNA-damaging agents or ionizing radiation and cause subsequent cell apoptosis., In addition, a large body of clinical evidence suggests that such patients may exhibit survival benefits when exposed to platinum-based chemotherapy regimens, including cisplatin, oxaliplatin, and carboplatin, compared to those who receive nonplatinum combinations., Six-month treatment with FOLFIRINOX, a platinum-containing combination therapy (oxaliplatin, irinotecan, fluorouracil, and leucovorin), has been suggested as a standard of care for advanced pancreatic adenocarcinoma with BRCA1/ 2 mutations.,
Novel agents such as poly(ADP-ribose) polymerase (PARP) enzyme inhibitors are molecules that inhibit the activity of PARPs involved in various DNA damage repair pathways, which separate histones from DNA and enable DNA repair. The accumulation of DNA damage due to the lack of DNA repair mechanisms by PARP inhibitors has been shown to result in mitotic catastrophe and subsequent tumor cell death. In clinical trials on patients with a germline BRCA2 mutation, response rates of approximately 40% have been recorded with olaparib for recurrent breast and 31% for ovarian cancers.,,, Pancreatic cancer cells with BRCA2 mutations are also sensitive to PARP inhibitors. A randomized, double-blind, placebo-controlled phase 3 (POLO) trial which evaluated the efficacy of olaparib as maintenance therapy in patients with a germline BRCA1/ 2 mutation showed no progression of metastatic pancreatic cancer or disease during first-line platinum-based chemotherapy. In addition, the median progression-free survival was significantly longer in the patient group (7.4 months) than in the placebo group (3.8 months). The antitumor activity of PARP inhibitor maintenance treatment after first-line chemotherapy was demonstrated in this population and may have been considered as an onward treatment option for our patient.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient has given his consent for his images and other clinical information to be reported in the journal. The patient understand that name and initials will not be published and due efforts will be made to conceal identity, but anonymity cannot be guaranteed.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Liede A, Karlan BY, Narod SA. Cancer risks for male carriers of germline mutations in BRCA1 or BRCA2: A review of the literature. J Clin Oncol 2004;22:735-42.
Holter S, Borgida A, Dodd A, Grant R, Semotiuk K, Hedley D, et al.
Germline BRCA mutations in a large clinic-based cohort of patients with pancreatic adenocarcinoma. J Clin Oncol 2015;33:3124-9.
Domchek SM, Hendifar AE, McWilliams RR, Geva R, Epelbaum R, Biankin A, et al
. RUCAPANC: An open-label, phase 2 trial of the PARP inhibitor rucaparib in patients (pts) with pancreatic cancer (PC) and a known deleterious germline or somatic BRCA mutation. J Clin Oncol 2016;34 Suppl 15:4110.
Golan T, Kanji ZS, Epelbaum R, Devaud N, Dagan E, Holter S, et al.
Overall survival and clinical characteristics of pancreatic cancer in BRCA mutation carriers. Br J Cancer 2014;111:1132-8.
Lowery MA, Kelsen DP, Stadler ZK, Yu KH, Janjigian YY, Ludwig E, et al.
An emerging entity: Pancreatic adenocarcinoma associated with a known BRCA mutation: Clinical descriptors, treatment implications, and future directions. Oncologist 2011;16:1397-402.
van der Heijden MS, Brody JR, Dezentje DA, Gallmeier E, Cunningham SC, Swartz MJ, et al
. In vivo
therapeutic responses contingent on Fanconi anemia/BRCA2 status of the tumor. Clin Cancer Res 2005;11:7508-15.
Yoshida K, Miki Y. Role of BRCA1 and BRCA2 as regulators of DNA repair, transcription, and cell cycle in response to DNA damage. Cancer Sci 2004;95:866-71.
King MC, Marks JH, Mandell JB, New York Breast Cancer Study Group. Breast and ovarian cancer risks due to inherited mutations in BRCA1 and BRCA2. Science 2003;302:643-6.
Gershoni-Baruch R, Dagan E, Fried G, Bruchim Bar-Sade R, Sverdlov-Shiri R, Zelicksson G, et al.
Significantly lower rates of BRCA1/BRCA2 founder mutations in Ashkenazi women with sporadic compared with familial early onset breast cancer. Eur J Cancer 2000;36:983-6.
Hodgson SV, Heap E, Cameron J, Ellis D, Mathew CG, Eeles RA, et al.
Risk factors for detecting germline BRCA1 and BRCA2 founder mutations in Ashkenazi Jewish women with breast or ovarian cancer. J Med Genet 1999;36:369-73.
Sung PL, Wen KC, Chen YJ, Chao TC, Tsai YF, Tseng LM, et al.
The frequency of cancer predisposition gene mutations in hereditary breast and ovarian cancer patients in Taiwan: From BRCA1/2 to multi-gene panels. PLoS One 2017;12:e0185615.
Kang E, Seong MW, Park SK, Lee JW, Lee J, Kim LS, et al.
The prevalence and spectrum of BRCA1 and BRCA2 mutations in Korean population: Recent update of the Korean hereditary breast cancer (KOHBRA) study. Breast Cancer Res Treat 2015;151:157-68.
Nakamura S, Takahashi M, Tozaki M, Nakayama T, Nomizu T, Miki Y, et al.
Prevalence and differentiation of hereditary breast and ovarian cancers in Japan. Breast Cancer 2015;22:462-8.
Daly MB, Pilarski R, Berry M, Buys SS, Farmer M, Friedman S, et al.
NCCN guidelines insights: Genetic/Familial high-risk assessment: Breast and ovarian, version 2.2017. J Natl Compr Canc Netw 2017;15:9-20.
Castro E, Goh C, Olmos D, Saunders E, Leongamornlert D, Tymrakiewicz M, et al.
Germline BRCA mutations are associated with higher risk of nodal involvement, distant metastasis, and poor survival outcomes in prostate cancer. J Clin Oncol 2013;31:1748-57.
Mavaddat N, Barrowdale D, Andrulis IL, Domchek SM, Eccles D, Nevanlinna H, et al.
Pathology of breast and ovarian cancers among BRCA1 and BRCA2 mutation carriers: Results from the consortium of investigators of modifiers of BRCA1/2 (CIMBA). Cancer Epidemiol Biomarkers Prev 2012;21:134-47.
Spurdle AB, Healey S, Devereau A, Hogervorst FB, Monteiro AN, Nathanson KL, et al.
ENIGMA − Evidence-based network for the interpretation of germline mutant alleles: An international initiative to evaluate risk and clinical significance associated with sequence variation in BRCA1 and BRCA2 genes. Hum Mutat 2012;33:2-7.
Cline MS, Liao RG, Parsons MT, Paten B, Alquaddoomi F, Antoniou A, et al.
BRCA challenge: BRCA exchange as a global resource for variants in BRCA1 and BRCA2. PLoS Genet 2018;14:e1007752.
Tan DS, Kaye SB. Chemotherapy for patients with BRCA1 and BRCA2-mutated ovarian cancer
: Same or different?
Am Soc Clin Oncol Educ Book 2015. p. 114-21.
Chappuis PO, Goffin J, Wong N, Perret C, Ghadirian P, Tonin PN, et al.
A significant response to neoadjuvant chemotherapy in BRCA1/2 related breast cancer. J Med Genet 2002;39:608-10.
Waddell N, Pajic M, Patch AM, Chang DK, Kassahn KS, Bailey P, et al.
Whole genomes redefine the mutational landscape of pancreatic cancer. Nature 2015;518:495-501.
Peddi PF, Lubner S, McWilliams R, Tan BR, Picus J, Sorscher SM, et al.
Multi-institutional experience with FOLFIRINOX in pancreatic adenocarcinoma. JOP 2012;13:497-501.
Conroy T, Desseigne F, Ychou M, Bouché O, Guimbaud R, Bécouarn Y, et al.
FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med 2011;364:1817-25.
Vincent A, Herman J, Schulick R, Hruban RH, Goggins M. Pancreatic cancer. Lancet 2011;378:607-20.
Konecny GE, Kristeleit RS. PARP inhibitors for BRCA1/2-mutated and sporadic ovarian cancer: Current practice and future directions. Br J Cancer 2016;115:1157-73.
Kaufman B, Shapira-Frommer R, Schmutzler RK, Audeh MW, Friedlander M, Balmaña J, et al.
Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation. J Clin Oncol 2015;33:244-50.
Audeh MW, Carmichael J, Penson RT, Friedlander M, Powell B, Bell-McGuinn KM, et al.
Oral poly (ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and recurrent ovarian cancer: A proof-of-concept trial. Lancet 2010;376:245-51.
Tutt A, Robson M, Garber JE, Domchek SM, Audeh MW, Weitzel JN, et al.
Oral poly (ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and advanced breast cancer: A proof-of-concept trial. Lancet 2010;376:235-44.
Golan T, Hammel P, Reni M, Van Cutsem E, Macarulla T, Hall MJ, et al.
Maintenance olaparib for germline BRCA-mutated metastatic pancreatic cancer. N Engl J Med 2019;381:317-27.