Emerging strategies in BRCA-positive pancreatic cancer

Purpose We propose a treatment algorithm for PDAC with particular emphasis on BRCA1 or 2 mutation-positive patients. Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest diseases in the United States and Europe. BRCA1 and BRCA2 are among the most common of the known genetic mutations involved in familial PDAC. The optimal chemotherapy regimen to use for BRCA1 or 2 mutation carriers with PDAC is not yet established. As new treatment options emerge, algorithms must balance the need to give the best drugs first with ensuring that there are still beneficial options available for later. Methods We conducted a review of the literature for data on possible therapies in BRCA-positive and BRCA-negative pancreatic cancer. Results There is accumulating evidence of increased sensitivity to platinum-based therapy and poly-ADP-ribose polymerase inhibitors (PARPi) in BRCA-associated PDAC. There are no studies relating to borderline BRCA-associated PDAC and, therefore, same treatment as for sporadic PDAC seems appropriate. Treatment of unresectable PDAC varies depending on stage of the disease. Patients with BRCA-associated locally advanced PDAC can benefit from targeted therapy with PARPi (olaparib) as a second-line therapy after antimetabolite treatment failure. Patients with unresectable metastatic BRCA-positive PDAC may benefit from platinum-based therapy. Conclusion Targeted therapies are shifting the treatment paradigms and increasing survival for patients with PDAC, a group that used to have a grim prognosis.


Introduction
Pancreatic cancer is one of the deadliest diseases in the United States and Europe, and the fourth leading cause of cancer-related death (Von Hoff et al. 2013). Of all pancreatic cancers, 95% are adenocarcinomas of the ductal epithelium. The 5-year survival rate for patients with stage IA exocrine pancreatic cancer is about 14%, while in IV stage it does not exceed 1% (Surgery for Pancreatic Cancer 2016). The identification of molecular mechanism associated with pancreatic carcinogenesis is of utmost importance for understanding the nature of pancreatic cancer (Beger et al. 2004). A family history of pancreatic cancer is found in 5-10% of pancreatic cancer patients (Klein 2012). Pancreatic ductal adenocarcinoma (PDAC) occurs especially in families with ovarian or breast cancers (Golan et al. 2014).
BRCA1 and BRCA2 are the most common of the known genetic mutations involved in familial pancreatic cancer (Leung and Saif 2013). Family studies have demonstrated that both BRCA1 and BRCA2 mutation carriers have an increased risk of developing pancreatic cancer (Beger et al. 2004). In case of BRCA1 mutation carriers the relative risk for pancreatic cancer is 3.1 and 6.6 in relatives of BRCA2 mutations carriers (Iqbal et al. 2012). Somatic genomic analysis has identified four specific subtypes of pancreatic adenocarcinoma stable, locally rearranged, scattered and unstable (Biankin and Maitra 2015).
BRCA1 and BRCA2 mutations are related to the unstable subtype exhibiting a unique mutational signature reflecting Adam Kowalewski and Łukasz Szylberg contributed equally. DNA damage repair deficiency (Golan et al. 2014). The emergence of molecular tests allows us to tailor treatment strategies based on the presence of driver mutations.
Patients with breast or ovarian BRCA -related cancer now benefit from targeted therapies in the first line and beyond. However, the optimal chemotherapy regimen to use for BRCA1 or 2 mutation carriers with PDAC is not yet established. As new treatment options emerge, algorithms must balance the need to give the best drugs first with ensuring that there are still beneficial options available for later. This paper discusses treatment approaches for patients with unresectable PDAC, especially in patients with BRCA -related PDAC.
Mutations of these genes may play a pivotal role in tumor genesis and cancer progression (Zhu et al. 2017).
Prevalence of BRCA1 and BRCA2 mutations fluctuates between 1 in 300 and 1 in 800 and depends on the population. There are more than 2000 known mutations in BRCA1 or 2 genes. In some populations founder mutations are the most frequent. For example, about 2.5% of the general Ashkenazi Jewish population will harbor mutation of BRCA1. The founder mutations also occur in Northern, Western and Eastern Europe. For that time penetration is variable and not expressly understood (Paluch-Shimon et al. 2016).
Cells with reduced activity of BRCA1 or 2 proteins accumulate double-strand breaks that cause genomic instability and consequently increased predisposition to malignant transformation and progression. Somatic, biallelic inactivation of the BRCA1 or 2 genes confers sensitivity to inhibition of poly(ADP-ribose)-polymerase (PARP), an enzyme involved in base excision repair (Beger et al. 2004).
Cell with dysfunction in BRCA1 or 2 genes use less accurate mechanism to repair double-strand breaks which increase the probability of cell death (Solomon and Everett 1990).

Discussion
The optimal chemotherapy regimen to use for BRCA1 or 2 mutation carriers with pancreatic adenocarcinoma is not established. Ryan et al. suggest using the same chemotherapy regimens in the adjuvant setting as are used for nonmutation carriers (Ryan et al. 2018). However, there is accumulating evidence of increased sensitivity to platinum-based therapy and poly-ADP-ribose polymerase inhibitors (PARPi) in BRCA -associated PDAC (Ryan et al. 2018).
Among tested agents these two represent a promising alternative for BRCA-associated PDAC. Seven studies (Golan et al. 2014;Oettle et al. 2014;Kaufman et al. 2015;Wu et al. 2015;Hurt et al. 2017;Kobayashi et al. 2017;Xu et al. 2017) that investigated a predictive role of BRCA1 or 2 mutation among patients with pancreatic cancer are summarized in Table 1. Most of them showed significantly enhanced response to DNA damage-related agents.

Platinum agents
In three studies (Oettle et al. 2014;Kaufman et al. 2015;Hurt et al. 2017), there was reported significantly improved OS and response to platinum-based treatment in BRCA-positive PDAC. Platinum-based anticancer drugs bind directly to DNA, causing DNA double-strand breaks. Therefore, cells that lack BRCA1 or BRCA2 have a deficiency in the repair of DNA double-strand breaks (Lohse et al. 2016).

PARP inhibitors
The PARP enzymes play critical roles in DNA damage detection and repair (de Bono et al. 2017).
PARP1 is a protein that is important for repairing singlestrand breaks. If the breaks persist unrepaired until DNA is replicated, then the replication itself can cause double-strand breaks to form. PARP1 inhibitors cause multiple double-strand breaks to form in this way, and in tumors with BRCA1 or 2 mutations, these double-strand breaks cannot be efficiently repaired, leading to death of the cells (Vinayak and Ford 2010).

Resection
In the early stage of PDAC, surgery offers the only realistic chance for recovery (Surgery for Pancreatic Cancer 2016). Regardless of the use of platinum compounds or PARPi, the prognosis of surgically resectable BRCA -associated PDAC is no different than that of sporadic PDAC (Golan et al. 2017). There are no studies relating to borderline BRCA -associated PDAC and, therefore, same treatment as for sporadic PDAC seems appropriate (Lopez et al. 2014). Treatment of unresectable PDAC varies depending on stage of the disease. In the following, we separate locally advanced from metastatic tumors.

First-line therapy
There are no studies confirming the greater efficiency of any alternative therapy in patients with unresectable locally advanced BRCA -related PDAC as a first-line therapy. Antimetabolites appear to be the best option as a first-line therapy. Hurt et al. tested the activity and safety of gemcitabinebased and capecitabine-based chemoradiation for locally advanced pancreatic cancer. mOS was 17.6 months among patients treated with capecitabine-based chemoradiation vs 14.6 months among patients with gemcitabine-based chemoradiation. Also mPFS was higher in group treated with capecitabine-based chemoradiaton (12.0 vs 10.4 months in group treated with gemcitabine-based chemoradiation) (Hurt et al. 2017).

Second-line therapy
Patients with BRCA -associated locally advanced pancreatic cancer can benefit from targeted therapy with PARP inhibitor (olaparib) as a second-line therapy after antimetabolite treatment failure. Leung and Saif described an example of two patients with BRCA2-associated pancreatic cancer treated with PARP inhibitors. Patients achieved partial or complete response with non-significant side effects (Leung and Saif 2013). The distinct sensitivity of cancerous cells to PARPi (olaparib) was also observed in study of Lowery et al. (2011). Among 16 cases, 11 had BRCA2-associated PDAC. Three out of four patients receiving PARPi and five out of six patients receiving platinum-based chemotherapy demonstrated an initial radiographic partial response. Unfortunately, each patient treated with a PARP inhibitor experienced progression of disease after several months of therapy. It was probably caused by acquired resistance to PARP inhibition.
Similar study showed that tumor response rate for patients treated with PARPi was 21.7%. OS in this group was 9.8 months and PFS was 4.6 months. Severe side effects (grade 3 or 4) were observed in 30.4% of patients. There was no significant difference in response rate for those treated previously with platinum or between BRCA1 and BRCA2 mutation. Type of mutation appeared to be not as important as previously suspected. Moreover, prior platinum treatment does not improve patients' outcomes (Kaufman et al. 2015). Oettle et al. used oxaliplatin, folinic acid (FA) and fluorouracil (FU) also after gemcitabine therapy failure. The data regarding BRCA mutation are not applicable. OS in this group was 5.9 months and PFS was 2.9 months. Severe side effects (grade 3 or 4) were observed in 43% of patients (Oettle et al. 2014).

Third-line therapy
There is no established third-line therapy for patients with BRCA -positive PDAC. We suggest using the standard second-line treatment. Treatment with oxiplatine together with FA and FU as a second line, results in OS of 5.9 months (Oettle et al. 2014).

First-line therapy
Patients with unresectable metastatic BRCA -positive PDAC may benefit from platinum-based therapy. Golan et al. compared platinum-based therapy vs non-platinum chemotherapies in patients with BRCA -positive pancreatic cancer in stage III/IV. Median overall survival (mOS) in patients treated with platinum agents was higher comparing to those treated with non-platinum chemotherapies (22 vs 9 months, P = 0.039). This study also showed that probability of OS in patients treated with platinum is 0.7 in 12 months and 0.16 in 36 months. Probability of OS in patients treated with non-platinum chemotherapy is 0.26 in 12 months and 0.07 in 36 months (Golan et al. 2014).

Second-line therapy
There is no established second-line therapy for patients with BRCA -positive PDAC after platinum-based therapy. Therefore, treatment with gemcitabine with paclitaxel or erlotynib or capecitabine is a reasonable option. Xu et al. conducted a study using gemcitabine with paclitaxel in patients with metastatic pancreatic cancer. In this study, mOS was 9.2 months and median progression-free survival (PFS) was 5.5 months. The most common grade ≥ 3 adverse events were leukopenia (35%), neutropenia (34%), anemia (15%), thrombocytopenia (10%), and fatigue (13%) (Xu et al. 2017).

Third-line therapy
There is no established third-line therapy for patients with BRCA -positive PDAC. Selection of the therapy after gemcitabine treatment failure depends on patient's condition and life expectancy. Kobayashi et al. studied the effectiveness of FOLFIRINOX in patients with metastatic pancreatic cancer after gemcitabine treatment failure. Among 18 patients receiving FOLFIRINOX, mOS was 9.8 months and PFS was 2.8 months (Kobayashi et al. 2017). Because of high rate of serious side effects (78%), such treatment is recommended especially in patients in good health. Wu et al. studied the effectiveness of lapatinib and capecitabine in patients with metastatic pancreatic cancer after gemcitabine treatment failure. mOS and PFS was lower than after FOLFIRINOX (5.2 vs 9.8 months and 2.6 vs 2.8 months, respectively). However, serious side effects were observed only in 18% of patients (Wu et al. 2015) . This is why lapatinib and capecitabine seem the most accurate in patients with serious side effects after gemcitabine treatment.

Conclusions
Our understanding of PDAC mutations and their contribution to therapeutic efficacy is expanding. The treatment selection is complex, with new target therapies being developed. Because BRCA1 and BRCA2 mutations are relatively rare in the general population, testing should be performed especially when the person's individual or family history suggests the possible presence of a harmful mutation in 1 3 BRCA1 or BRCA2. For patients with locally advanced PDAC with BRCA1 or 2 mutation who have progressed on capecitabine, new treatment options to improve survival include PARP inhibitors such as olaparib. For patients with metastatic PDAC with BRCA1 or 2 mutation, platinum-based therapy can lead to significant improvements in survival. Targeted therapies are shifting the treatment paradigms and increasing survival for patients with PDAC, a group that used to have a grim prognosis. We propose a treatment algorithm for PDAC with particular emphasis on BRCA1 or 2 mutation-positive patients (Fig. 1).
Author contributions All authors contributed in a manuscript as well as figure preparation are thoroughly familiar with its present version and are able to defend its content and conclusions.

Compliance with ethical standards
Conflict of interest The authors declare that they have no conflict of interest.
Ethical approval This article does not contain any studies with human participants or animals performed by any of the authors.
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