224 Clinical report
Clinical outcomes in pancreatic adenocarcinoma associated with BRCA-2 mutation Ojas Vyasa, Keith Leunga, Leslie Ledbetterb, Kristin Kaleyc, Teresa Rodriguezd, Marie C. Garcond and Muhammad W. Saifa Patients with BRCA-1 and BRCA-2 germ line mutations are at an increased risk of developing pancreatic adenocarcinoma (PAC). In particular, the BRCA-2 mutation has been associated with a relative risk of developing PAC of 3.51. The BRCA-2 protein is involved in repair of doublestranded DNA breaks. Recent reports have suggested that in the setting of impaired DNA repair, chemotherapeutic agents that induce DNA damage, such as platinum-based antineoplastic drugs (platins) and poly(ADP-ribose) polymerase inhibitors (PARP inhibitors), have improved efficacy. However, because of the relative rarity of BRCArelated PAC, studies evaluating such agents in this setting are scarce. Patients with a known BRCA-2 mutation and PAC were retrospectively reviewed. Ten patients with PAC and BRCA-2 mutation were identified. Four patients (40%) were of Ashkenazi Jewish descent. Seven patients (70%) received platinum agents, two (20%) received mitomycin-C, one (10%) received a PARP inhibitor, and seven (70%) received a topoisomerase-I inhibitor. Overall, chemotherapy was well tolerated with expected side effects. Patients with
a BRCA-2 mutation and PAC represent a group with a unique biology underlying their cancer. Chemotherapies such as platinum derivatives, mitomycin-C, topoisomerase-I inhibitors, and PARP inhibitors targeting DNA require further investigation in this population. Genetic testing may guide therapy in the future. Anti-Cancer Drugs 26:224–226 © 2015 Wolters Kluwer Health | Lippincott Williams & Wilkins. Anti-Cancer Drugs 2015, 26:224–226 Keywords: BRCA, chemotherapy, genetics, pancreatic cancer a Tufts University School of Medicine and Tufts Medical Center, Boston, Massachusetts, bUniversity of Alabama at Birmingham (UAB), Birmingham, Alabama, cYale New Haven Hospital, New Haven, Connecticut and dColumbia University Medical Center, New York, New York, USA
Correspondence to Muhammad W. Saif, MD, MBBS, Cancers and Experimental Therapeutics, Tufts University School of Medicine, 800 Washington Street, Boston, MA 02111, USA Tel: + 1 617 636 5627; fax: + 1 617 636 8535; e-mail: [email protected] Received 17 July 2014 Revised form accepted 5 September 2014
Background
Patients and methods
Pancreatic malignancy is the fourth most common cause of cancer death in the USA and is associated with a poor prognosis. The American Cancer Society estimates that there will be 39 590 deaths in 2014 from this disease [1]. Of the known genetic predispositions to pancreatic malignancy, BRCA mutations are the most frequently observed. Patients with a BRCA mutation are at a greater than two-fold risk for pancreatic cancer [2]. In particular, the BRCA-2 mutation has been associated with a relative risk for pancreatic malignancy of 3.51 [3]. The BRCA-2 protein enables repair of double-stranded DNA breaks through homologous recombination [4]. Recent reports have suggested that in the setting of impaired DNA repair chemotherapeutic agents that induce DNA damage have improved efficacy. Ovarian cancer patients with a BRCA mutation show improved response to platinum-based therapy [5,6]. Poly(ADP-ribose) polymerase (PARP) inhibitors also appear uniquely efficacious against tumors in the presence of BRCA mutations [7]. In addition, topoisomerase-I inhibitors and mitomycin-C have both shown promise in this setting [8,9]. However, because of the relative rarity of BRCA-related pancreatic adenocarcinomas (PACs), studies evaluating this disease have been limited and are usually small [10,11]. We have collected data on 10 cases to add to the literature.
Ten patients with a known BRCA-2 mutation and PAC were identified in a retrospective chart review. Data on epidemiologic factors such as age, sex, ethnic background, history of prior malignancy, and staging at diagnosis were collected. Treatment regimens and treatment response were also identified.
0959-4973 © 2015 Wolters Kluwer Health | Lippincott Williams & Wilkins
Results Ten patients with BRCA-2 mutations and PAC were identified. Their demographics are summarized in Table 1. Seven patients (70%) received platinum-based therapy, two (20%) received mitomycin-C, one (10%) received a PARP inhibitor, and seven (70%) received a topoisomerase-I inhibitor. Their responses to chemotherapy are summarized in Table 2. Overall, chemotherapy was well tolerated, with Table 1 Demographics of patients with BRCA-2 mutation and pancreatic adenocarcinoma Male Female Age (median, mean) (years) Ashkenazi heritage Stage IV at diagnosis History of malignancy
3 (30) 7 (70) 57, 56 4 (40) 8 (80) 4 (40) DOI: 10.1097/CAD.0000000000000178
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Prostate
DOR, duration of response; FOLFIRI, 5-fluorouracil, leucovorin, and irinotecan; GTX, gemcitabine, docetaxel, capecitabine; m-FOLFOX6, 5-fluorouracil, leucovorin, and oxaliplatin; PARP, poly(ADP-ribose) polymerase; XRT, radiation therapy. a Discontinued due to hypersensitivity reaction. b Developed cholangitis during week 3 of the first cycle and ultimately passed away on day 39 of diagnosis. c Patient received one dose of oxaliplatin with mitomycin-C, but oxaliplatin was discontinued because of a hypersensitivity reaction.
57 56 97 208 9; 8 16; 12; 8 56; 9 9 Capecitabine; tamoxifen FOLFIRI; ironotecan; erlotinib FOLFIRI; ironotecan–erlotinib Mitomcyin-Cc 16 8 24 133 Exatecan PARP inhibitor CO-101 Irinotecan, irinotecan–cetuximab N/Ab 32 12 8 66 Gemcitabine–hedgehog Inhibitor Gemcitabine–cisplatin Gemcitabine–docetaxel–capecitabine Gemcitabine–hedgehog Inhibitor Gemcitabine–docetaxel–capecitabine IV IV IV IV IV M F F M M 58 59 62 68 71
Breast
120 74 76 41 80 8 12 16 12; 12; 8 Irinotecan Capecitabine Capecitabine–oxaliplatin Mitomycin-C; docetaxel; docetaxel–erlotinib 12 32 16 24 40 m-FOLFOX6 Gemcitabine–oxaliplatin Gemcitabine–cisplatin Docetaxel–irinotecan Capecitabine–erlotinib Breast Breast
Stage of PAC Personal history of cancer Age Sex
Summary of patients Table 2
Evidence continues to grow suggesting that therapies capable of exploiting the inability of BRCA carriers to repair double-stranded DNA breaks may yield an improved outcome among these patients [11,12]. Platinum-based chemotherapy results in DNA cross-linking, to which BRCAdeficient cells appear to be hypersensitive [13]. The small size of our cohort limits our ability to extrapolate from our outcomes. In a recent meta-analysis [14], the median progression-free survival in second-line therapy for all patients with pancreatic cancer treated with gemcitabine and platinum combination therapy was 4 months. Patients
First-line therapy
Previously, one of the largest series of patients with pancreatic cancer and BRCA mutations consisted of only 15 patients. Of the patients in that study, 73% had an underlying BRCA-2 mutation. Of the patients in our study, 40% had a prior history of malignancy compared with 60% in the previously published study. In our study, 80% of patients presented with metastatic disease, as opposed to 53% in the study by Lowery and colleagues. The difference in patient characteristics may be partially attributable to their collection of patients with either BRCA-1 or BRCA-2 mutations.
108 34 48 N/Aa 8
DOR (weeks)
Pancreatic cancer associated with BRCA mutations is an intriguing clinical entity that is currently being studied for its potential therapeutic targets. Our understanding of this disease has been limited by the probable underdiagnosis of the mutation in these patients. Genetic testing in patients with pancreatic cancer is not commonplace. Increased testing of patients with pancreatic malignancy would increase our understanding of the disease and potentially guide chemotherapeutic choices.
Distal pancreatectomy and gemcitabine Capecitabine and XRT Gemcitabine–irinotecan Gemcitabine–NADPH inhibitor Gemcitabine–oxaliplatin
Second-line therapy
Discussion
II III IV IV IV
DOR (weeks)
Third-line and other therapies
DOR (weeks)
Among the six patients who tolerated platinumcontaining combination therapy, the range of DOR to these agents was 8–32 weeks, with a mean DOR of 19.3 weeks. Two patients who received platinum-based therapy as first-line therapy in combination with gemcitabine had DORs of 32 and 8 weeks. Among the three patients who tolerated platinum-based therapy as secondline therapy, the DOR ranged from 12–16 weeks, with a mean of 14.7 weeks. Only one patient was treated with a PARP inhibitor. She was diagnosed with metastatic PAC and was treated with GTX (gemcitabine, docetaxel, capecitabine) for 12 weeks and then with a PARP inhibitor as second-line therapy, with a DOR of 8 weeks. For the seven patients receiving topoisomerase-I inhibitors alone or in combination, the mean and median DORs were 33 and 16 weeks, respectively. The range of response varied widely between patients, from 8 to 133 weeks. The two patients who were exposed to mitomycin-C responded for 9 and 12 weeks, respectively.
F F F F F
expected side effects. The mean and median total durations of response (DORs) to all chemotherapies for all patients were 89.9 and 76 weeks, respectively (range: 41–208).
46 42 47 56 56
Duration of disease control (weeks)
BRCA and pancreatic cancer Vyas et al. 225
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
226 Anti-Cancer Drugs 2015, Vol 26 No 2
treated with 5-FU-based and platinum-derived combinations had a progression-free survival of 2.9 months. Our three BRCA-positive patients treated with platinum-derived agents as second-line therapy had a similar time to progression as the patients in the meta-analysis. Further research is needed to determine whether the benefit seen with platinum-based chemotherapy in other BRCA-related malignancies applies to PAC. Another promising group of drugs are PARP inhibitors, which inhibit base excision repair, resulting in singlestrand DNA breaks. These breaks cause further instability, resulting in double-stranded DNA breaks typically repaired by homologous recombination. In the case of BRCA deficiency, failure of this pathway sensitizes cells to PARP inhibitors [15]. Pancreatic cancer models have demonstrated the chemotherapeutic rationale for these agents in BRCA-2 deficiency [16]. Here, we note only one patient who received a PARP inhibitor and had an 8-week DOR. There is limited published data on the efficacy of PARP inhibitors in pancreatic cancer. Topoisomerase-I inhibitors and mitomycin-C also have a theoretical benefit in the presence of BRCA mutations. Here, we present a variety of clinical responses including that in a patient who had 81 weeks of stable disease with irinotecan and then another 52 weeks before progression on irinotecan in combination with cetuximab. Two patients above were treated with mitomycin-C as well. The role of these agents in BRCA-related malignancy and particularly PAC remains to be clearly defined. Patients with BRCA-2-positive pancreatic malignancy may represent a group with a biology unique to their malignancy. In particular, they may benefit from a treatment approach targeted toward their underlying DNA repair deficiencies that would limit drug toxicity. Current data on this population remains limited and inconclusive. Awareness on this entity and more frequent testing for BRCA mutations could further our understanding. Given the poor prognosis of pancreatic cancer, further investigation into therapy that targets this subgroup is warranted.
Acknowledgements Conflicts of interest
There are no conflicts of interest.
References 1 2
3 4 5
6
7
8
9
10
11
12
13
14
15
16
American Cancer Society. Cancer Facts & Figures 2014. Atlanta, GA: American Cancer Society; 2014. Iqbal J, Ragone A, Lubinski J, Lynch HT, Moller P, Ghadirian P, et al. Hereditary Breast Cancer Study Group. The incidence of pancreatic cancer in BRCA1 and BRCA2 mutation carriers. Br J Cancer 2012; 107:2005–2009. The Breast Cancer Linkage Consortium. Cancer risks in BRCA2 mutation carriers. J Natl Cancer Inst 1999; 91:1310–1316. Moynahan ME, Pierce AJ, Jasin M. BRCA2 is required for homology-directed repair of chromosomal breaks. Mol Cell 2001; 7:263–272. Tan DS, Rothermundt C, Thomas K, Bancroft E, Eeles R, Shanley S, et al. “BRCAness” syndrome in ovarian cancer: a case-control study describing the clinical features and outcome of patients with epithelial ovarian cancer associated with BRCA1 and BRCA2 mutations. J Clin Oncol 2008; 26:5530–5536. Dann RB, DeLoia JA, Timms KM, Zorn KK, Potter J, Flake DD 2nd, et al. BRCA1/2 mutations and expression: response to platinum chemotherapy in patients with advanced stage epithelial ovarian cancer. Gynecol Oncol 2012; 125:677–682. Fong PC, Boss DS, Yap TA, Tutt A, Wu P, Mergui-Roelvink M, et al. Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N Engl J Med 2009; 361:123–134. Moynahan ME, Cui TY, Jasin M. Homology-directed DNA repair, mitomycin-c resistance, and chromosome stability is restored with correction of a Brca1 mutation. Cancer Res 2001; 61:4842–4850. James E, Waldron-Lynch MG, Saif MW. Prolonged survival in a patient with BRCA2 associated metastatic pancreatic cancer after exposure to camptothecin: a case report and review of literature. Anticancer Drugs 2009; 20:634–638. Ferrone CR, Levine DA, Tang LH, Allen PJ, Jarnagin W, Brennan MF, et al. BRCA germline mutations in Jewish patients with pancreatic adenocarcinoma. J Clin Oncol 2009; 27:433–438. 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; 16:1397–1402. Cass I, Baldwin RL, Varkey T, Moslehi R, Narod SA, Karlan BY. Improved survival in women with BRCA-associated ovarian carcinoma. Cancer 2003; 97:2187–2195. 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; 11:7508–7515. Rahma OE, Duffy A, Liewehr DJ, Steinberg SM, Greten TF. Second-line treatment in advanced pancreatic cancer: a comprehensive analysis of published clinical trials. Ann Oncol 2013; 24:1972–1979. Farmer H, McCabe N, Lord CJ, Tutt AN, Johnson DA, Richardson TB, et al. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature 2005; 434:917–921. Porcelli L, Quatrale AE, Mantuano P, Leo MG, Silvestris N, Rolland JF, et al. Optimize radiochemotherapy in pancreatic cancer: PARP inhibitors a new therapeutic opportunity. Mol Oncol 2013; 7:308–322.
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Clinical outcomes in pancreatic adenocarcinoma associated with BRCA-2 mutation Ojas Vyasa, Keith Leunga, Leslie Ledbetterb, Kristin Kaleyc, Teresa Rodriguezd, Marie C. Garcond and Muhammad W. Saifa Patients with BRCA-1 and BRCA-2 germ line mutations are at an increased risk of developing pancreatic adenocarcinoma (PAC). In particular, the BRCA-2 mutation has been associated with a relative risk of developing PAC of 3.51. The BRCA-2 protein is involved in repair of doublestranded DNA breaks. Recent reports have suggested that in the setting of impaired DNA repair, chemotherapeutic agents that induce DNA damage, such as platinum-based antineoplastic drugs (platins) and poly(ADP-ribose) polymerase inhibitors (PARP inhibitors), have improved efficacy. However, because of the relative rarity of BRCArelated PAC, studies evaluating such agents in this setting are scarce. Patients with a known BRCA-2 mutation and PAC were retrospectively reviewed. Ten patients with PAC and BRCA-2 mutation were identified. Four patients (40%) were of Ashkenazi Jewish descent. Seven patients (70%) received platinum agents, two (20%) received mitomycin-C, one (10%) received a PARP inhibitor, and seven (70%) received a topoisomerase-I inhibitor. Overall, chemotherapy was well tolerated with expected side effects. Patients with
a BRCA-2 mutation and PAC represent a group with a unique biology underlying their cancer. Chemotherapies such as platinum derivatives, mitomycin-C, topoisomerase-I inhibitors, and PARP inhibitors targeting DNA require further investigation in this population. Genetic testing may guide therapy in the future. Anti-Cancer Drugs 26:224–226 © 2015 Wolters Kluwer Health | Lippincott Williams & Wilkins. Anti-Cancer Drugs 2015, 26:224–226 Keywords: BRCA, chemotherapy, genetics, pancreatic cancer a Tufts University School of Medicine and Tufts Medical Center, Boston, Massachusetts, bUniversity of Alabama at Birmingham (UAB), Birmingham, Alabama, cYale New Haven Hospital, New Haven, Connecticut and dColumbia University Medical Center, New York, New York, USA
Correspondence to Muhammad W. Saif, MD, MBBS, Cancers and Experimental Therapeutics, Tufts University School of Medicine, 800 Washington Street, Boston, MA 02111, USA Tel: + 1 617 636 5627; fax: + 1 617 636 8535; e-mail: [email protected] Received 17 July 2014 Revised form accepted 5 September 2014
Background
Patients and methods
Pancreatic malignancy is the fourth most common cause of cancer death in the USA and is associated with a poor prognosis. The American Cancer Society estimates that there will be 39 590 deaths in 2014 from this disease [1]. Of the known genetic predispositions to pancreatic malignancy, BRCA mutations are the most frequently observed. Patients with a BRCA mutation are at a greater than two-fold risk for pancreatic cancer [2]. In particular, the BRCA-2 mutation has been associated with a relative risk for pancreatic malignancy of 3.51 [3]. The BRCA-2 protein enables repair of double-stranded DNA breaks through homologous recombination [4]. Recent reports have suggested that in the setting of impaired DNA repair chemotherapeutic agents that induce DNA damage have improved efficacy. Ovarian cancer patients with a BRCA mutation show improved response to platinum-based therapy [5,6]. Poly(ADP-ribose) polymerase (PARP) inhibitors also appear uniquely efficacious against tumors in the presence of BRCA mutations [7]. In addition, topoisomerase-I inhibitors and mitomycin-C have both shown promise in this setting [8,9]. However, because of the relative rarity of BRCA-related pancreatic adenocarcinomas (PACs), studies evaluating this disease have been limited and are usually small [10,11]. We have collected data on 10 cases to add to the literature.
Ten patients with a known BRCA-2 mutation and PAC were identified in a retrospective chart review. Data on epidemiologic factors such as age, sex, ethnic background, history of prior malignancy, and staging at diagnosis were collected. Treatment regimens and treatment response were also identified.
0959-4973 © 2015 Wolters Kluwer Health | Lippincott Williams & Wilkins
Results Ten patients with BRCA-2 mutations and PAC were identified. Their demographics are summarized in Table 1. Seven patients (70%) received platinum-based therapy, two (20%) received mitomycin-C, one (10%) received a PARP inhibitor, and seven (70%) received a topoisomerase-I inhibitor. Their responses to chemotherapy are summarized in Table 2. Overall, chemotherapy was well tolerated, with Table 1 Demographics of patients with BRCA-2 mutation and pancreatic adenocarcinoma Male Female Age (median, mean) (years) Ashkenazi heritage Stage IV at diagnosis History of malignancy
3 (30) 7 (70) 57, 56 4 (40) 8 (80) 4 (40) DOI: 10.1097/CAD.0000000000000178
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Prostate
DOR, duration of response; FOLFIRI, 5-fluorouracil, leucovorin, and irinotecan; GTX, gemcitabine, docetaxel, capecitabine; m-FOLFOX6, 5-fluorouracil, leucovorin, and oxaliplatin; PARP, poly(ADP-ribose) polymerase; XRT, radiation therapy. a Discontinued due to hypersensitivity reaction. b Developed cholangitis during week 3 of the first cycle and ultimately passed away on day 39 of diagnosis. c Patient received one dose of oxaliplatin with mitomycin-C, but oxaliplatin was discontinued because of a hypersensitivity reaction.
57 56 97 208 9; 8 16; 12; 8 56; 9 9 Capecitabine; tamoxifen FOLFIRI; ironotecan; erlotinib FOLFIRI; ironotecan–erlotinib Mitomcyin-Cc 16 8 24 133 Exatecan PARP inhibitor CO-101 Irinotecan, irinotecan–cetuximab N/Ab 32 12 8 66 Gemcitabine–hedgehog Inhibitor Gemcitabine–cisplatin Gemcitabine–docetaxel–capecitabine Gemcitabine–hedgehog Inhibitor Gemcitabine–docetaxel–capecitabine IV IV IV IV IV M F F M M 58 59 62 68 71
Breast
120 74 76 41 80 8 12 16 12; 12; 8 Irinotecan Capecitabine Capecitabine–oxaliplatin Mitomycin-C; docetaxel; docetaxel–erlotinib 12 32 16 24 40 m-FOLFOX6 Gemcitabine–oxaliplatin Gemcitabine–cisplatin Docetaxel–irinotecan Capecitabine–erlotinib Breast Breast
Stage of PAC Personal history of cancer Age Sex
Summary of patients Table 2
Evidence continues to grow suggesting that therapies capable of exploiting the inability of BRCA carriers to repair double-stranded DNA breaks may yield an improved outcome among these patients [11,12]. Platinum-based chemotherapy results in DNA cross-linking, to which BRCAdeficient cells appear to be hypersensitive [13]. The small size of our cohort limits our ability to extrapolate from our outcomes. In a recent meta-analysis [14], the median progression-free survival in second-line therapy for all patients with pancreatic cancer treated with gemcitabine and platinum combination therapy was 4 months. Patients
First-line therapy
Previously, one of the largest series of patients with pancreatic cancer and BRCA mutations consisted of only 15 patients. Of the patients in that study, 73% had an underlying BRCA-2 mutation. Of the patients in our study, 40% had a prior history of malignancy compared with 60% in the previously published study. In our study, 80% of patients presented with metastatic disease, as opposed to 53% in the study by Lowery and colleagues. The difference in patient characteristics may be partially attributable to their collection of patients with either BRCA-1 or BRCA-2 mutations.
108 34 48 N/Aa 8
DOR (weeks)
Pancreatic cancer associated with BRCA mutations is an intriguing clinical entity that is currently being studied for its potential therapeutic targets. Our understanding of this disease has been limited by the probable underdiagnosis of the mutation in these patients. Genetic testing in patients with pancreatic cancer is not commonplace. Increased testing of patients with pancreatic malignancy would increase our understanding of the disease and potentially guide chemotherapeutic choices.
Distal pancreatectomy and gemcitabine Capecitabine and XRT Gemcitabine–irinotecan Gemcitabine–NADPH inhibitor Gemcitabine–oxaliplatin
Second-line therapy
Discussion
II III IV IV IV
DOR (weeks)
Third-line and other therapies
DOR (weeks)
Among the six patients who tolerated platinumcontaining combination therapy, the range of DOR to these agents was 8–32 weeks, with a mean DOR of 19.3 weeks. Two patients who received platinum-based therapy as first-line therapy in combination with gemcitabine had DORs of 32 and 8 weeks. Among the three patients who tolerated platinum-based therapy as secondline therapy, the DOR ranged from 12–16 weeks, with a mean of 14.7 weeks. Only one patient was treated with a PARP inhibitor. She was diagnosed with metastatic PAC and was treated with GTX (gemcitabine, docetaxel, capecitabine) for 12 weeks and then with a PARP inhibitor as second-line therapy, with a DOR of 8 weeks. For the seven patients receiving topoisomerase-I inhibitors alone or in combination, the mean and median DORs were 33 and 16 weeks, respectively. The range of response varied widely between patients, from 8 to 133 weeks. The two patients who were exposed to mitomycin-C responded for 9 and 12 weeks, respectively.
F F F F F
expected side effects. The mean and median total durations of response (DORs) to all chemotherapies for all patients were 89.9 and 76 weeks, respectively (range: 41–208).
46 42 47 56 56
Duration of disease control (weeks)
BRCA and pancreatic cancer Vyas et al. 225
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
226 Anti-Cancer Drugs 2015, Vol 26 No 2
treated with 5-FU-based and platinum-derived combinations had a progression-free survival of 2.9 months. Our three BRCA-positive patients treated with platinum-derived agents as second-line therapy had a similar time to progression as the patients in the meta-analysis. Further research is needed to determine whether the benefit seen with platinum-based chemotherapy in other BRCA-related malignancies applies to PAC. Another promising group of drugs are PARP inhibitors, which inhibit base excision repair, resulting in singlestrand DNA breaks. These breaks cause further instability, resulting in double-stranded DNA breaks typically repaired by homologous recombination. In the case of BRCA deficiency, failure of this pathway sensitizes cells to PARP inhibitors [15]. Pancreatic cancer models have demonstrated the chemotherapeutic rationale for these agents in BRCA-2 deficiency [16]. Here, we note only one patient who received a PARP inhibitor and had an 8-week DOR. There is limited published data on the efficacy of PARP inhibitors in pancreatic cancer. Topoisomerase-I inhibitors and mitomycin-C also have a theoretical benefit in the presence of BRCA mutations. Here, we present a variety of clinical responses including that in a patient who had 81 weeks of stable disease with irinotecan and then another 52 weeks before progression on irinotecan in combination with cetuximab. Two patients above were treated with mitomycin-C as well. The role of these agents in BRCA-related malignancy and particularly PAC remains to be clearly defined. Patients with BRCA-2-positive pancreatic malignancy may represent a group with a biology unique to their malignancy. In particular, they may benefit from a treatment approach targeted toward their underlying DNA repair deficiencies that would limit drug toxicity. Current data on this population remains limited and inconclusive. Awareness on this entity and more frequent testing for BRCA mutations could further our understanding. Given the poor prognosis of pancreatic cancer, further investigation into therapy that targets this subgroup is warranted.
Acknowledgements Conflicts of interest
There are no conflicts of interest.
References 1 2
3 4 5
6
7
8
9
10
11
12
13
14
15
16
American Cancer Society. Cancer Facts & Figures 2014. Atlanta, GA: American Cancer Society; 2014. Iqbal J, Ragone A, Lubinski J, Lynch HT, Moller P, Ghadirian P, et al. Hereditary Breast Cancer Study Group. The incidence of pancreatic cancer in BRCA1 and BRCA2 mutation carriers. Br J Cancer 2012; 107:2005–2009. The Breast Cancer Linkage Consortium. Cancer risks in BRCA2 mutation carriers. J Natl Cancer Inst 1999; 91:1310–1316. Moynahan ME, Pierce AJ, Jasin M. BRCA2 is required for homology-directed repair of chromosomal breaks. Mol Cell 2001; 7:263–272. Tan DS, Rothermundt C, Thomas K, Bancroft E, Eeles R, Shanley S, et al. “BRCAness” syndrome in ovarian cancer: a case-control study describing the clinical features and outcome of patients with epithelial ovarian cancer associated with BRCA1 and BRCA2 mutations. J Clin Oncol 2008; 26:5530–5536. Dann RB, DeLoia JA, Timms KM, Zorn KK, Potter J, Flake DD 2nd, et al. BRCA1/2 mutations and expression: response to platinum chemotherapy in patients with advanced stage epithelial ovarian cancer. Gynecol Oncol 2012; 125:677–682. Fong PC, Boss DS, Yap TA, Tutt A, Wu P, Mergui-Roelvink M, et al. Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N Engl J Med 2009; 361:123–134. Moynahan ME, Cui TY, Jasin M. Homology-directed DNA repair, mitomycin-c resistance, and chromosome stability is restored with correction of a Brca1 mutation. Cancer Res 2001; 61:4842–4850. James E, Waldron-Lynch MG, Saif MW. Prolonged survival in a patient with BRCA2 associated metastatic pancreatic cancer after exposure to camptothecin: a case report and review of literature. Anticancer Drugs 2009; 20:634–638. Ferrone CR, Levine DA, Tang LH, Allen PJ, Jarnagin W, Brennan MF, et al. BRCA germline mutations in Jewish patients with pancreatic adenocarcinoma. J Clin Oncol 2009; 27:433–438. 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; 16:1397–1402. Cass I, Baldwin RL, Varkey T, Moslehi R, Narod SA, Karlan BY. Improved survival in women with BRCA-associated ovarian carcinoma. Cancer 2003; 97:2187–2195. 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; 11:7508–7515. Rahma OE, Duffy A, Liewehr DJ, Steinberg SM, Greten TF. Second-line treatment in advanced pancreatic cancer: a comprehensive analysis of published clinical trials. Ann Oncol 2013; 24:1972–1979. Farmer H, McCabe N, Lord CJ, Tutt AN, Johnson DA, Richardson TB, et al. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature 2005; 434:917–921. Porcelli L, Quatrale AE, Mantuano P, Leo MG, Silvestris N, Rolland JF, et al. Optimize radiochemotherapy in pancreatic cancer: PARP inhibitors a new therapeutic opportunity. Mol Oncol 2013; 7:308–322.
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
