Management of patients with pancreatic carcinoma carrying BRCA gene mutations

SUMMARY

Pancreatic ductal adenocarcinoma (PDAC, hereinafter referred to as pancreatic cancer) is a type of cancer with a poor prognosis with a 5-year survival rate of 7% in all stages. Most patients are diagnosed at a late stage and the median overall survival (OS) is short. The response of pancreatic cancer to conventional treatments is limited, in part because of its genetic heterogeneity. Molecular biology efforts have been made to classify pancreatic cancer into different subgroups. The subtype due to defective DNA damage repair (DDR) or destabilized genes/DSBR (double-strand DNA break repair), is one of the most clinically significant biological abnormalities in pancreatic cancer. Certain genetic syndromes increase the risk of pancreatic cancer and occur in about 10% of pancreatic cancer patients. Updates to the ASCO and NCCN clinical practice guidelines have recommended a risk assessment for all patients with pancreatic cancer, regardless of patient history, family, or race. DNA repair dysfunction associated with germline BRCA mutations (gBRCAm) exemplifies one of the subgroups of PDAC. This genetic variation can be inhibited by PARP inhibitor (PARPi) therapy. Treatment indications for pancreatic cancer with germline BRCA mutations include platinum-based chemotherapy and maintenance treatment with PARPi in platinum-sensitive patients. In the era of personalized treatment, this is the first convincing example of targeted treatment of germline genetic mutations identified in pancreatic cancer.

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Source of article: https://jnccn.org/view/journals/jnccn/19/4/article-p469.xml?rskey=szQemw&result=7

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OVERVIEW

Pancreatic ductal adenocarcinoma (PDAC) is one of the most malignant solid tumors. Most patients are diagnosed at a late stage and cannot undergo surgery. Overall survival (OS) in stage IV patients is very low [1,2]. Overall survival typically ranges from 4 to 11 months, although rates are slightly higher in patients enrolled in clinical trials; real-life data on overall survival are limited. mechanism [3-5]. The treatment of pancreatic cancer is challenging, especially in patients who, at the time of diagnosis, are already experiencing severe health deterioration such as weight loss, diffuse abdominal pain, anorexia, depression, reduced physical activity [6]. Furthermore, pancreatic carcinoma is resistant to chemotherapy; patients who receive first-line treatment with combination chemotherapy regimens have a progression-free survival (PFS) of less than 4 to 6 years. months and response rates below 40% [5,7].

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To improve the management of pancreatic cancer in the era of personalized medicine, it is important to identify patient groups that may benefit from targeted therapy (or targeted therapy). Specifically, the germline BRCA ½ mutation (gBRCAm) affects 7% of pancreatic cancer patients [8]. BRCA1/2 proteins play an important role in the repair of double-strand DNA breaks (DSBs). Tumors with mutations in homologous recombination repair (HRR) genes such as BRCA 1/2 are sensitive to chemotherapy regimens containing platinum and PARP inhibitors (PARPi) [9].

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The group of chemicals (carboplatin, cisplatin and oxaliplatin) causes DNA damage by creating covalent bonds between bases in DNA. The cytotoxic effects of these agents depend on the number and specific structure of DNA adducts [10]. Treatment with platinum-based chemicals showed higher efficacy and response rates to platinum salts in tumor cells lacking the double-stranded DNA break (DSB) repair machinery. PARP inhibition leaves single-strand DNA breaks (SSBs) unrepaired. Single-strand breaks at the replication fork (site of double helix opening and DNA synthesis) cause fork opening, and can cause fork collapse or double-strand DNA breaks. In the absence of the repair protein BRCA1/2, forks cannot form and replication stops. The mechanism of PARP inhibitors also includes "retaining" the PARP-1 protein at the site of DNA damage, leading to PARP-1 protein deficiency as well as the mobilization of repair proteins, causing the accumulation of DNA complexes. cause cytotoxicity [9].

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Based on the understanding of BRCA proteins and their essential role in DNA repair, germline BRCA mutations (gBRCAm) are a valuable biomarker to predict the effectiveness of platinum-based chemotherapy. . In 2005, on the basis of specific inhibition and preclinical data, PARPi was included as a treatment option in early phase clinical trials for tumors with BRCA mutations. [11].

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Data from ovarian cancer clinical trials have shed light on the role of PARPi in solid tumors. Studies on the use of PARPi in the treatment of ovarian cancer and other solid tumors have shown cross-resistance between platinum groups and PARPi in cases with gBRCAm mutations [12-16]. This suggests that PARPi should be included in maintenance therapy to maximize drug efficacy and achieve stable disease (e.g. in cases of stable disease or partial response to chemotherapy). , more effective polychemotherapy (e.g., 5-FU/irinotecan/oxaliplatin [FOLFIRINOX]) has improved disease control. This has facilitated a shift in treatment strategies, including the development of maintenance treatment regimens that maintain disease stability without affecting patient quality of life (QoL). such as using treatments that are less toxic than platinum-based chemotherapy. In particular, retrospective data on pancreatic adenocarcinoma have shown that median overall survival (OS) in patients with gBRCAm mutations is as poor as in patients with adenocarcinoma. Pancreatic tissue is not hereditary. Some retrospective data suggest that pancreatic cancer patients with gBRCAm receiving platinum-based chemotherapy may have durable responses and prolonged overall survival. This is also shown by recent retrospective and prospective clinical data. This shows that although gBRCAm is a biomarker with predictive value, it is not prognostic [17-19].

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Testing PARPi treatment in patients with pancreatic carcinoma faces many difficulties. Firstly, there is no accurate information about the incidence, as well as the possibility of geographical/ethnic differences of the gBRCAm mutation being unclear, making it difficult to establish clinical trials. Furthermore, it is unclear whether biologically guided maintenance therapy can be evaluated in cases of metastatic pancreatic cancer with extremely short overall survival.

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The 2014 phase III POLO study evaluated the efficacy of PARPi olaparib as maintenance treatment after first-line platinum-based chemotherapy compared with placebo in patients with metastatic pancreatic cancer with gBRCAm [20]. Patients must have received at least 16 weeks of platinum-based first-line chemotherapy and achieved disease control. The study's selection criteria did not limit the duration of chemotherapy to help facilitate the recruitment of study subjects. The study design included an initial recruitment phase to select suitable patients with metastatic pancreatic carcinoma. Of the 3,315 patients participating in this recruitment process, 7.5% of patients were found to carry gBRCAm, including 1.5% of patients who were diagnosed with this mutation before participating in the trial. About two-thirds of patients with pancreatic carcinoma have gBRCA2m and one-third of patients have gBRCA1m, while most patients with ovarian or breast cancer have BRCA1 mutations.

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In the POLO trial, 38% of patients were ineligible for maintenance treatment most likely due to disease progression while on first-line platinum-based chemotherapy (nearly 30%). These patients may have innate (primary) resistance to DNA-damaging chemotherapy despite the presence of gBRCAm, for example due to acquisition of a reversion mutation that downregulates the ATR/CHK1 pathway (ATR: proteinkinase specifically involved in detecting damaged DNA and activating DNA repair tools, it phosphorylates Chk1) or restores the formation of RAD51.

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As a result, 154 patients eligible to participate in the POLO trial were randomized into the olaparib group at a dose of 300 mg x twice daily and the placebo group at a ratio of 3:2, with maintenance treatment until disease resolution. progression or unacceptable toxicity.

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Progression-free survival (PFS) was the primary endpoint, assessed by a blinded independent center. This progression-free survival time is calculated from the time the patient is randomized to the equivalent after completing first-line chemotherapy. Secondary criteria include: time to second disease progression, rate of objective response rate (ORR), health-related quality of life (HrQoL), safety and tolerability, and overall survival (OS). The initial analysis suggested 87 PFS events giving the study the power to detect 80% of the difference between groups with a one-sided test of a=0.025.

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Characteristics of patients in the 2 groups were similar. Multivariate analysis showed that small differences between the 2 groups did not affect the progression-free survival (PFS) results. One-third of patients receiving olaparib remained on treatment at the time data collection stopped (January 15, 2019).

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The primary endpoint (PFS) was 7.4 months in the olaparib group and 3.8 months in the placebo group (HR=0.53; p=0.0038). The proportion of patients whose disease did not progress at 6, 12, 18, and 24 months was also analyzed. From month 6 onwards, the proportion of patients with disease progression in the olaparib group was always twice as high as in the placebo group, HR = 0.53. All subgroup analyzes showed a progression-free survival benefit in the olaparib arm. Another interesting finding was that PFS in the olaparib arm did not differ between patients whose disease was stable and those who responded to first-line chemotherapy.

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At the time of baseline progression-free survival analysis, overall survival (OS) was also analyzed. Median overall survival (OS) was 18.9 months in the olaparib group and 18.1 months in the placebo group (HR= 0.91). Further treatments as the tumor progresses (mainly retreatment with chemotherapy) may affect the overall survival results in this study. Notably, 14.5% of patients in the placebo group continued to receive PARPi treatment outside of the study design. Final overall survival will be analyzed after 106 deaths.

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STRATEGIES IN TREATMENT OF PANCREASAL CARcinoma WITH MUTATIONS

The objective response rate (ORR) in patients was 11.5% for the placebo group and 23.1% for the olaparib group, with 2 complete responses. The relatively early onset of responses in the placebo group suggests that these responses were influenced by first-line platinum chemotherapy.

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In the POLO trial, the median duration of response (DoR) was 6 months, but in a small group of patients (23%) with an objective response on imaging the survival was exceptional. lasting longer than up to over 24 months, an impressive number of metastatic pancreatic cancer. Quality of life assessed based on the EORTC QLQ-C30 questionnaire (scale from 1-100) during the first 6 months of treatment was not significantly impaired in patients using olaparib [21]. 40% of patients receiving olaparib had grade 3 or higher toxicity. However, only 5.5% of cases of severe toxicity required discontinuation of treatment. The median duration of treatment was 6 months in the olaparib group and 3.7 months in the placebo group. The toxicity of olaparib is similar to that when used to treat other diseases. The most common toxicities are fatigue, nausea, and diarrhea. Anemia and fatigue were the most common grade ≥3 toxicities.

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Other PARPi are being evaluated in patients with pancreatic carcinoma (Table 1). In a phase II study comparing mFOLFIRI + veliparib with FOLFIRI alone in step 2 (SWOGS1513) in patients with metastatic pancreatic cancer, the addition of veliparib increased toxicity and did not improve survival. overall in patients in general [22].

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In another study by O'Reilly et al [18], 50 pancreatic adenocarcinoma patients with gBRCA- or PALB2 mutations were randomized to receive gemcitabine (600 mg/m2) and cisplatin regimen. (25 mg/m2) on days 3 and 10 with or without veliparib (80 mg) taken orally twice daily from days 1 to 12 every 3 weeks. The response rate of patients in the veliparib group was not superior to that of the other groups (74.1% vs 65.2%; p=0.55). Median progression-free survival (PFS) was 10.1 months (95% CI, 6.7–11.5 months) and 9.7 months (95% CI, 4.2–13, respectively). 6 months; p =0.73); The median overall survival (OS) was 15.5 months (95% CI, 12.2–24.3 months) and 16.4 months (95% CI, 11.7–23.4 months), respectively. ;p=0.6). Overall, veliparib did not improve treatment outcomes and caused more grade 3-4 hematologic toxicity. This study highlights the valuable treatment effect of the gemcitabine + cisplatin combination regimen. However, it should be noted that unlike the POLO study, patients received first-line PARPi without selection from response to prior platinum-based chemotherapy.

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In the selection criteria of the POLO study there was no upper limit on the number of treatment cycles per patient. The decision to discontinue all or part of the chemotherapy regimen was at the discretion of the clinician. Based on the time from diagnosis to randomization in the POLO study (6.9 months [range 3.6–38.4 months]), the duration of chemotherapy discontinuation is approximately 6 months. month. However, based on the study design and trial results, this issue needs to be discussed between doctors and patients. Furthermore, at the time of study initiation, the results of the PANOPTIMOX study (as yet unpublished) comparing maintenance 5-FU with continued use of FOLFIRINOX (reported at the 2018 ASCO conference) cannot be evaluated yet (NCT02352337); on the other hand, no studies have evaluated the role of maintenance FOLFIRI or capecitabine.

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PARPi resistance is a challenge in pancreatic cancer treatment. In the POLO study, approximately 40% of patients who achieved disease control had primary resistance to olaparib. In the future, analyzing circulating cell-free DNA (ccfDNA) to find reversible mutations of BRCA may help guide treatment [23]. On the other hand, combining PARPi with other drugs such as checkpoint inhibitors and bromodomain and extraterminal domain (BET) inhibitors such as JQ1 may increase the effectiveness of PARPi [24].

Finally, there is a need to evaluate the value of PARPi and manage progression with olaparib in pancreatic cancer with rarer BRCAness mutations (e.g., PALB2, RAD51, ATM) or somatic mutations that leads to HRR deficiency.

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CONCLUSION

The POLO study provides the first evidence of targeted maintenance therapy in patients with pancreatic adenocarcinoma. First, combining PARPi with chemotherapy is challenging due to concerns about drug toxicity. Another issue is that if platinum resistance predicts PARPI resistance, when is the time to add PARPi? The maintenance treatment strategy is based on the higher response rate to cytotoxic chemotherapy coupled with the lower toxicity of PARPi compared with long-term chemotherapy. There was a statistically significant increase in progression-free survival (PFS) with PARPi compared with placebo, and a significant number of patients achieved disease control for >2 years while improving quality of life ( QoL) is still guaranteed. Although the study population is limited, the positive results of this phase III trial will change treatment practice in pancreatic carcinoma patients with gBRCAm. Olaparib was approved by the FDA for maintenance therapy on December 27, 2019.

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These study results confirm the importance of testing for BRCA and other germline mutations in all patients with pancreatic adenocarcinoma and are now recommended in both the ASCO and ASCO guidelines. NCCN [25,26]. The strategy of first-line platinum-based chemotherapy followed by maintenance with olaparib will become the new standard of care in patients with metastatic pancreatic carcinoma with a germline BRCA mutation (gBRCAm).

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Table 1. Clinical trials: PARPi in pancreatic carcinoma