Next Article in Journal
Enhancing Intrapleural Hyperthermic Chemotherapy for Lung Cancer: Insights from 3D and PDX Models
Next Article in Special Issue
Preclinical Multi-Omic Assessment of Pioglitazone in Skeletal Muscles of Mice Implanted with Human HER2/neu Overexpressing Breast Cancer Xenografts
Previous Article in Journal
Clinical and Histopathological Features of Thyroid Cancer with TERT Promoter Molecular Alterations in Isolation Versus with Concurrent Molecular Alterations: A Multicenter Retrospective Study
Previous Article in Special Issue
Vascular Biomarkers for Pulmonary Nodule Malignancy: Arteries vs. Veins
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Cancers
Volume 16
Issue 20
10.3390/cancers16203447
cancers-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Article

PARP Inhibitors in Pancreatic Cancer with Homologous Recombination Repair Gene Mutations: A Single-Institution Experience

by
Ruoyu Miao
1,
Kirsten Blue
1,
Katelyn Sommerer
1,
Anand Shah
1,
Sal Bottiglieri
1,
Alex del Cueto
2,
Darcy K. Berry
2,
Teresa T. Ho
2,
James Kevin Hicks
2 and
Dae Won Kim
1,*
1
Department of Gastrointestinal Oncology, Moffitt Cancer Center, Tampa, FL 33612, USA
2
Department of Pathology, Moffitt Cancer Center, Tampa, FL 33612, USA
*
Author to whom correspondence should be addressed.
Cancers 2024, 16(20), 3447; https://doi.org/10.3390/cancers16203447
Submission received: 1 September 2024 / Revised: 30 September 2024 / Accepted: 7 October 2024 / Published: 11 October 2024
(This article belongs to the Collection Oncology: State-of-the-Art Research in the USA)
Browse Figure
Review Reports Versions Notes

Abstract

:

Simple Summary

The anticancer activity of PARP inhibitors in pancreatic cancer with mutations in HRR genes other than BRCA and PALB2 remains inconclusive. The authors retrospectively reviewed the clinical characteristics and outcomes of patients with advanced pancreatic cancer harboring pathogenic germline and/or somatic HRR mutations who were treated with PARP inhibitors. PARP inhibitors may be considered for patients with advanced pancreatic cancer harboring pathogenic alterations of BRCA who cannot tolerate standard chemotherapy. Maintenance PARP inhibitor therapy may be considered in selected patients with non-BRCA and non-PALB2 HRR mutations.

Abstract

Background: Limited data are available regarding the anticancer activity of PARP inhibitors (PARPis) in pancreatic cancer with mutations in HRR genes other than BRCA and PALB2. Methods: We retrospectively reviewed the clinical characteristics and outcomes of 48 patients with advanced pancreatic cancer harboring pathogenic germline and/or somatic HRR mutations who were treated with PARPis. Results: Thirty patients had germline (g)HRR mutations only, twelve had somatic (s)HRR mutations only, and six had concomitant gHRR and sHRR mutations. The objective response rate (ORR) was 22%. The median progression-free survival (mPFS) and overall survival (mOS) were 6.9 and 11.5 months, respectively. Five patients received olaparib in the front-line setting due to borderline performance status. Their ORR was 20%, and their mPFS and mOS were both 11.3 months. The ORR was higher in patients with BRCA or PALB2 mutations (germline or somatic) than in those with non-BRCA/PALB2 mutations. Patients with somatic non-BRCA/PALB2 variants had a shorter mPFS. Patients with concomitant gHRR/sHRR mutations or gHRR mutations alone had a significantly longer mPFS than those with sHRR mutations only. Conclusions: PARP inhibitors may be considered for patients with advanced pancreatic cancer harboring pathogenic alterations of BRCA who cannot tolerate standard chemotherapy. Maintenance PARPis can be considered in selected patients with non-BRCA/non-PALB2 HRR mutations.

1. Introduction

Poly (ADP-ribose) polymerase (PARP) is an essential enzyme for the repair of DNA damage including strand breaks which frequently occur during cell proliferation. PARP inhibitors catalytically inhibit PARP and trap PARP on damaged DNA which subsequently stop replication forks from continuing. In normal cells, this would be fixed by homologous recombination (HR). However, in HR-deficient tumor cells, alternative error-prone DNA repair pathways may lead to DNA fragmentation and ultimately cell death [1,2,3,4]. Therefore, PARP inhibition is an attractive therapeutic approach in HR-deficient cancer. Approximately 20% of patients with pancreatic cancer have homologous recombination repair (HRR) gene mutations including BRCA1, BRCA2, PALB2, ATM, BAP1, BARD1, BLM, BRIP1, CHEK2, FAM175A, FANCA, FANCC, NBN, RAD50, RAD51, RAD51C, and RTEL1 [5,6,7,8]. A PARP inhibitor, olaparib, has demonstrated significantly improved progression-free survival (PFS) in patients with metastatic castration-resistant prostate cancer harboring deleterious alterations of HRR genes including BRCA1, BRCA2, ATM, BRIP1, BARD1, CDK12, CHEK1, CHEK2, FANCL, PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D, and RAD54L [9]. In metastatic pancreatic adenocarcinoma, maintenance olaparib prolonged PFS in patients with pathogenic alterations in germline BRCA1 or BRCA2 compared to the placebo (7.4 months vs. 3.8 months) in the phase 3 POLO trial [10,11]. In the single-arm phase 2 trial of maintenance rucaparib in patients with pathogenic alterations in germline or somatic BRCA1, BRCA2, or PALB2, the median PFS was 13.1 months, and the response rate was 41% in patients with pathogenic alterations in germline BRCA2, 50% with germline PALB2, and 50% with germline BRCA2 [12]. However, limited data are available regarding the anticancer activity of PARP inhibitors in other HRR-gene-mutated pancreatic cancers. In this study, we conducted a retrospective review of patients with HRR-gene-mutated pancreatic adenocarcinoma treated with PARP inhibitors at our institution.

2. Materials and Methods

2.1. Patient Selection and Clinical Data Collection

We retrospectively reviewed all patients with advanced pancreatic adenocarcinoma harboring pathogenic germline or somatic mutations in HRR genes who were treated with PARP inhibitors that started between 1 March 2018 and 31 July 2023 at Moffitt Cancer Center. Eligible patients were identified from pharmacies. The assays that were used to identify somatic HRR mutations included our in-house next-generation sequencing (NGS) assay (Moffitt Star) [13] and commercial NGS assays including FoundationOne® CDx (Foundation Medicine, Cambridge, MA, USA), CARIS® MI Tumor Seek Hybrid™ (Caris Life Sciences, Irving, TX, USA), FoundationOne® Liquid CDx (liquid biopsy; Foundation Medicine, Cambridge, MA, USA), and Guardant360® CDx (liquid biopsy; Guardant Health, Redwood City, CA, USA). Broad panel testing through Invitae® (Invitae Corpo-ration, San Francisco, CA, USA), Myriad Genetics® (Myriad Genetics, Salt Lake City, UT, USA), or Ambry Genetics® (Ambry Genetics, Aliso Viejo, CA, USA) was used to identify germline HRR mutations. A comprehensive chart review was completed for each eligible patient utilizing the electronic health record. Patient demographics, primary tumor characteristics, and treatment and clinical outcomes were collected. The study cut-off date was 15 March 2024. This study was reviewed and approved by the Institutional Review Board at Moffitt Cancer Center.

2.2. Treatment Assessment

Treatment response was assessed according to Response Evaluation Criteria in Solid Tumors (RECISTs) 1.1. An objective response rate (ORR) was defined as the percentage of patients who achieved complete response (CR) or partial response (PR). Disease control rate (DCR) was defined as the percentage of patients who achieved either complete response (CR), partial response (PR), or stable disease (SD). Progression-free survival (PFS) was defined as the time interval from the initiation of a PARP inhibitor to disease progression or death. Overall survival (OS) was defined as the time interval from the initiation of a PARP inhibitor to death from any cause or last-contact date.

2.3. Statistical Analysis

Statistical significance between groups was analyzed using the chi-square test or Fisher’s exact test for categorical variables and Student’s t-test or the Mann–Whitney U non-parametric test for continuous variables. The estimated PFS and OS were derived using the Kaplan–Meier method and compared by the Mantel–Cox log-rank test. The statistical analyses were performed using IBM SPSS Statistics for Windows, version 28.0 (IBM Corp, Armonk, NY, USA). Kaplan–Meier survival curves were generated in R (version 4.2.1; www.r-project.org (accessed on 6 June 2024)) using the “survminer” package and the “ggsurvplot” function. All reported p values were two-sided. The level of significance was set at p < 0.05.

3. Results

3.1. Patient Characteristics

A total number of 48 patients were identified. Patient demographics and characteristics are summarized in Table 1. The majority were male (54%) with a median age of 71 years (range: 42–90 years). Forty-seven patients received olaparib and one was treated with rucaparib. A PARP inhibitor was given to 9 patients (19%) with locally advanced disease and 39 patients (81%) with distant metastases. Five patients (10%) received a PARP inhibitor in the front-line setting due to borderline performance status (PS). The remaining 43 patients (90%) received it as maintenance after chemotherapy. Twenty-five patients received platinum-based chemotherapy and eighteen patients received non-platinum-based chemotherapy prior to maintenance PARP inhibitor administration.
Thirty-six patients were found to have pathogenic germline mutations in HRR genes, including BRCA2 (n = 11), ATM (n = 6), BRCA1 (n = 3), PALB2 (n = 3), FANCA (n = 3), NBN (n = 3), CHEK2 (n = 2), FANCM (n = 2), and RAD51C (n = 2), and one each in BARD1, BRIP1, FANCC, FANCG, and WRN (Table S1). Four patients had pathogenic germline mutations in two HRR genes (ATM/FANCC, BRCA2/BRIP1, BRCA2/NBN, and RAD51C/FANCA, respectively). Eighteen patients had pathogenic somatic mutations in HRR genes, including ATM (n = 7), BRCA2 (n = 5), and ARID1A (n = 3), and one each in BAP1, CHEK2, NBN, and PALB2. One patient was found to have pathogenic somatic mutations in two genes (ARID1A/NBN). Of note, six patients had concomitant pathogenic germline (g) mutation and somatic (s) mutation, including gATM/sATM, gBRCA2/sATM, gNBN/sBRCA2, gRAD51C/sARID1A, gPALB2/sBRCA2, and gPALB2/sPALB2.
Of the 34 patients with NGS results, 22 (65%) had somatic mutations in KRAS, most commonly KRAS G12V (n = 9, 26%), followed by KRAS G12D (n = 6, 18%), KRAS G12R (n = 3, 9%), KRAS Q61H (n = 3, 9%), and KRAS G12S (n =1, 3%). One patient (3%) was found to have NRAS G12D. The remaining 11 patients (33%) were RAS wild type (Table 1). sTP53 mutation was detected in 19 patients (56%). Nine patients (26%) had mutations in sCDKN2A/B.

3.2. Efficacy

Forty-six patients had follow-up scans that were evaluable for treatment response (Table 2). The overall ORR and DCR were 22% and 78%, respectively. Ten patients achieved partial response (PR, 22%), including two gBRCA2, one gBRCA1, one sBRCA2, one sATM, one gBRCA2/gBRIP1, one gBRCA2/sATM, one gPALB2/sBRCA2, one gPALB2/sPALB2, and one gNBN/sBRCA2. Stable disease (SD) was observed in twenty-six patients (57%), including five gBRCA2, three gATM, three sATM, two sBRCA2, two gCHEK2, two gFANCM, one gPALB2, one gFANCA, one gFANCG, one gWRN, one gNBN, one gBRCA2/gNBN, one gRAD51C/gFANCA, one gRAD51C/sARID1A, and one gATM/sATM. Progressive disease (PD) was found in 10 patients (22%). The ORR was the highest in the patients with concomitant germline and somatic HRR mutations (67%). Among the 28 patients with only germline HRR mutations, the ORR was 14% (29% in those with gBRCA or gPALB2 mutations and 0% in those with germline non-BRCA non-PALB2 mutations). Among the 12 patients with only somatic HRR mutations, the ORR was 17% (33% in those with sBRCA or sPALB2 mutations and 11% (1/9) in those with somatic non-BRCA non-PALB2 mutations) (Table 2).
For all patients, the median PFS was 6.9 months (95% confidence interval (CI): 3.4–10.4) and the median OS was 11.5 months (95% CI: 6.0–17.0) (Table 3). Patients with concomitant germline and somatic HRR mutations or germline HRR mutations alone had significantly longer PFS compared to those with somatic HRR mutations only (median: 10.2 vs. 8.3 vs. 3.0 months; p = 0.025) (Table 3 and Figure 1A). OS was numerically longer in patients with concomitant germline and somatic HRR mutations and germline HRR mutations only but was not statistically significant (median: 11.5 vs. 14.0 vs. 6.8 months; p = 0.101) (Table 3 and Figure 1B). Among patients with germline or somatic HRR mutations only, median PFS and OS were 6.1 months and 8.6 months among those with gBRCA or gPALB2 mutations, 8.3 months and 17.6 months with other germline HRR mutations, 12.2 months and 16.2 months with sBRCA or sPALB2 mutations, and 2.6 months and 5.9 months with somatic non-BRCA non-PALB2 mutations (Table 3, Figure 1C,D).
Among the 27 patients with non-BRCA and non-PALB2 HRR mutations, 15 had stable disease for over four months after initiation of a PARP inhibitor. There were two patients with concomitant germline and somatic HRR mutations (gATM/sATM, gRAD51C/sARID1A), one with two germline mutations (gRAD51C/gFANCA), nine with one germline mutation (three gATM, two gCHEK2, and one each for gWRN, gFANCA, gFANCM, and gNBN), and three with one somatic mutation (all sATM).

3.3. Maintenance after Chemotherapy

We identified patients who received non-platinum-based chemotherapy and were then switched to maintenance PARP inhibitors. We evaluated the efficacy of maintenance PARP inhibitors in this patient population.
PARP inhibitor therapy was given to 25 patients as maintenance following platinum-based chemotherapy and 18 patients following non-platinum-based chemotherapy. There were more patients with an Eastern Cooperative Oncology Group (ECOG) performance status (PS) score of 2, and fewer patients with an ECOG PS of 0 among those who received non-platinum-based chemotherapy (p = 0.003). There was no significant difference between maintenance after platinum-based and non-platinum-based chemotherapy in PFS (median: 5.1 vs. 10.2 months, p = 0.154) or OS (median: 11.5 vs. 14.0 months, p = 0.919) (Table 3). The ORR was 13% vs. 35% (p = 0.128) and the DCR was 67% vs. 88% (p = 0.152) (Table 4).

3.4. First Line for Borderline Performance Status

We identified five patients who received olaparib as first-line treatment, all with an ECOG PS of 2. One patient with gBRCA2/gBRIP1 mutations achieved PR and four achieved stable disease with gBRCA2 mutations (n = 2), a gBRCA2/gNBN mutation (n = 1), and an sATM mutation (n = 1). The ORR was 20% in patients who received first-line therapy and 22% among those who received a PARP inhibitor as maintenance. The DCR was 100% and 76%, the median PFS was 11.3 and 6.9 months, and the median OS was 11.3 and 11.5 months, respectively (Table 3, Figure 1E,F).

3.5. Treatment after Refractory to a PARP Inhibitor

Six patients received platinum-based chemotherapy, and twenty patients received non-platinum-based chemotherapy after disease progression on a PARP inhibitor. The median PFS and OS from initiation of subsequent line chemotherapy were 3.6 months (95% CI: 0.0–7.3 months) and 7.8 months (0.0–16.9 months), respectively, for patients who received platinum-based chemotherapy and 2.6 months (0.0–5.3 months) and 5.7 months (1.1–10.4 months), respectively, for non-platinum-based chemotherapy. A circulating tumor DNA (ctDNA) test was evaluated in one patient after refractory to a PARP inhibitor but we did not observe any reversion mutations of HRR genes.

4. Discussion

In this retrospective analysis, patients with germline HRR mutations achieved longer PFS compared to those with somatic HRR mutations. The least benefit in PFS was observed among patients with somatic non-BRCA/PALB2 mutations. Although not statistically significant, a similar trend was observed in OS. It has been reported that in metastatic breast cancer, patients with gPALB2 or sBRCA mutations derived similar benefits from PARP inhibition as those with gBRCA alterations [14,15]. A meta-analysis demonstrated comparable ORR of PARP inhibitors in patients with various malignancy types harboring somatic vs. germline BRCA mutations [16]. In pancreatic cancer specifically, there was a numerically increased response rate in somatic BRCA patients (3/4, 75%) compared to germline BRCA patients (7/32, 21.9%), although not statistically significant (p = 0.12) [16]. However, data may be underrepresented as many existing clinical trials for PARP inhibitors did not specifically include patients with somatic BRCA alterations [10,11,16]. We did not find a significant difference in the frequency of RAS, TP53, or CDKN2A mutations between germline vs. somatic HRR mutations or BRCA/PALB2 vs. non-BRCA/PALB2 mutations. Interestingly, we observed higher wild-type KRAS in this cohort than historical data which showed around 10% wild-type KRAS in pancreatic adenocarcinoma [17,18,19]. This may suggest that HRR mutations could be one of the major oncogenic driver mutations in wild-type KRAS pancreatic cancer.
We observed significant clinical benefits of PARP inhibitor therapy in select patients with pathogenic non-BRCA/PALB2 HRR mutations who achieved durable disease control. Most of these patients had germline HRR mutations, including gATM, gRAD51C, gFANCA, gCHEK2, gWRN, gFANCM, and gNBN, whereas all three patients with somatic mutation alone had sATM mutations. The frequency of RAS, TP53, or CDKN2A mutations was similar to that among the whole study cohort. Two parallel phase 2 nonrandomized clinical trials demonstrated a median PFS of 5.7 months and an OS of 13.6 months with olaparib monotherapy in patients with pretreated, advanced pancreatic cancer with DNA damage repair genetic alterations other than the germline BRCA variant, including gATM, sATM, gPALB2, sARID1A, sBRCA, sPTEN, sRAD51, sCCNE, and sFANCB. Partial response was reported in one patient harboring an sATM variant and one with a gPALB2 variant [20]. This finding is similar to our study. We observed a median PFS of 6.9 months and an OS of 11.5 months as a maintenance setting in this study. However, another tumor-agnostic phase 2 study showed no significant anticancer activity of olaparib in somatic or germline ATM- or CHEK2-mutated cancers, although only four patients with pancreatic cancer were enrolled [21]. This discrepancy may be related to additional molecular and genetic alterations and aberrations not discovered with current tests. Further studies are warranted to identify additional biomarkers to predict responses to PARP inhibitor therapy in this population.
Acquired reversion mutations in BRCA or PALB2 are uncommon but may restore the protein expression and potentially affect treatment outcomes including rapid progression on PARP inhibitors, resistance to subsequent platinum-based treatment, and poor overall survival [22,23,24,25,26]. In this study, only one patient was assessed for ctDNA after refractory to olaparib, but we did not observe any reversion mutations.
Several data points demonstrated clinical benefit of maintenance PARP inhibitor therapy [10,11,12,27,28,29]. However, the question remains as to whether the benefit during maintenance resulted from previous chemotherapy or purely from PARP inhibitor therapy, as maintenance requires at least stable disease from previous chemotherapy. In our study, objective responses were observed while on maintenance PARP inhibitors in several patients; therefore, the benefit can be inferred from PARP inhibitors.
Olaparib has been approved as a maintenance treatment for patients with gBRCA-mutated pancreatic cancer whose disease has not progressed on platinum-based chemotherapy. However, BRCA mutation status may not always be available before starting chemotherapy, and some patients cannot start platinum-based chemotherapy due to borderline or poor performance status. Currently, limited data are available for the efficacy of olaparib for this patient population. In our study, the maintenance olaparib after non-platinum-based chemotherapy and olaparib in the first-line setting for patients with borderline performance status showed comparable ORR, DCR, and survival benefit as maintenance treatment after platinum-based chemotherapy in BRCA-mutated pancreatic cancer, suggesting a potential benefit of olaparib in this patient population and clinical setting.
We have several limitations in this study. This is a retrospective study in a single institution with a limited number of patients. Very few patients with somatic BRCA/PALB2-mutated pancreatic cancer were enrolled in this study. In addition, patients in this study were selected based on different germline and/or somatic testing assays with different sensitivities, specificities, and number of targeted genes, and not all patients underwent both germline and somatic testing. Certain HRR mutations may be underestimated in our study. Further prospective studies with predefined germline and somatic testing assay(s) are needed to include other HRR alterations to verify our findings.

5. Conclusions

In summary, our study suggests that PARP inhibitors may be considered for patients with borderline performance status and advanced pancreatic cancer harboring pathogenic alterations of BRCA who cannot tolerate standard chemotherapy. Maintenance PARP inhibitors can also be considered even after non-platinum-based chemotherapy for patients with pathogenic BRCA-mutated pancreatic cancer. In addition, maintenance PARP inhibitor therapy may have clinical activity in selected patients with non-BRCA HRR-mutated pancreatic cancer. Further studies are needed to verify our findings, and further biomarker studies should be conducted to select patients with non-BRCA HRR-gene-mutated pancreatic cancer who may achieve clinical benefit from PARP inhibitors.
This article is a revised and expanded version of a paper entitled “PARP inhibitors in pancreatic cancer with homologous recombination repair gene mutations: A single-institution experience”, which was presented at the ESMO Gastrointestinal Cancers Congress 2024, in Munich, Germany, on 26–29 June 2024 [30].

Supplementary Materials

The following supporting information can be downloaded at https://www.mdpi.com/article/10.3390/cancers16203447/s1, Table S1: Mutated HRR genes.

Author Contributions

Conceptualization, R.M. and D.W.K.; data curation, R.M., K.B., K.S., A.S., S.B., A.d.C., D.K.B. and D.W.K.; formal analysis, R.M. and D.W.K.; funding acquisition, D.W.K.; supervision, D.W.K.; writing—original draft, R.M.; writing—review and editing, R.M., K.B., K.S., A.S., S.B., A.d.C., D.K.B., T.T.H., J.K.H. and D.W.K. All authors have read and agreed to the published version of the manuscript.

Funding

This research was supported by the Moffitt Foundation pancreatic cancer research fund (no number).

Institutional Review Board Statement

This study was conducted in accordance with the Declaration of Helsinki and approved by the Institutional Review Board of Moffitt Cancer Center (Pro00002818, approved on 26 January 2011).

Informed Consent Statement

Informed consent was obtained from all subjects involved in this study.

Data Availability Statement

The original contributions presented in this study are included in the article/Supplementary Materials. Further inquiries can be directed to the corresponding author/s.

Conflicts of Interest

The authors declare no conflicts of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of the data; in the writing of the manuscript; or in the decision to publish the results.

References

  1. Zheng, F.; Zhang, Y.; Chen, S.; Weng, X.; Rao, Y.; Fang, H. Mechanism and current progress of Poly ADP-ribose polymerase (PARP) inhibitors in the treatment of ovarian cancer. Biomed. Pharmacother. 2020, 123, 109661. [Google Scholar] [CrossRef] [PubMed]
  2. Das, P.K.; Matada, G.S.P.; Pal, R.; Maji, L.; Dhiwar, P.S.; Manjushree, B.V.; Viji, M. Poly (ADP-ribose) polymerase (PARP) inhibitors as anticancer agents: An outlook on clinical progress, synthetic strategies, biological activity, and structure-activity relationship. Eur. J. Med. Chem. 2024, 274, 116535. [Google Scholar] [CrossRef] [PubMed]
  3. Mateo, J.; Lord, C.J.; Serra, V.; Tutt, A.; Balmaña, J.; Castroviejo-Bermejo, M.; Cruz, C.; Oaknin, A.; Kaye, S.B.; de Bono, J.S. A decade of clinical development of PARP inhibitors in perspective. Ann. Oncol. 2019, 30, 1437–1447. [Google Scholar] [CrossRef]
  4. Lord, C.J.; Ashworth, A. PARP inhibitors: Synthetic lethality in the clinic. Science 2017, 355, 1152–1158. [Google Scholar] [CrossRef] [PubMed]
  5. Park, W.; Chen, J.; Chou, J.F.; Varghese, A.M.; Yu, K.H.; Wong, W.; Capanu, M.; Balachandran, V.; McIntyre, C.A.; El Dika, I.; et al. Genomic Methods Identify Homologous Recombination Deficiency in Pancreas Adenocarcinoma and Optimize Treatment Selection. Clin. Cancer Res. 2020, 26, 3239–3247. [Google Scholar] [CrossRef]
  6. Aguirre, A.J.; Nowak, J.A.; Camarda, N.D.; Moffitt, R.A.; Ghazani, A.A.; Hazar-Rethinam, M.; Raghavan, S.; Kim, J.; Brais, L.K.; Ragon, D.; et al. Real-time Genomic Characterization of Advanced Pancreatic Cancer to Enable Precision Medicine. Cancer Discov. 2018, 8, 1096–1111. [Google Scholar] [CrossRef]
  7. Casolino, R.; Paiella, S.; Azzolina, D.; Beer, P.A.; Corbo, V.; Lorenzoni, G.; Gregori, D.; Golan, T.; Braconi, C.; Froeling, F.E.M.; et al. Homologous Recombination Deficiency in Pancreatic Cancer: A Systematic Review and Prevalence Meta-Analysis. J. Clin. Oncol. 2021, 39, 2617–2631. [Google Scholar] [CrossRef]
  8. Heeke, A.L.; Pishvaian, M.J.; Lynce, F.; Xiu, J.; Brody, J.R.; Chen, W.-J.; Baker, T.M.; Marshall, J.L.; Isaacs, C. Prevalence of Homologous Recombination–Related Gene Mutations Across Multiple Cancer Types. JCO Precis. Oncol. 2018, 2, 1–13. [Google Scholar] [CrossRef]
  9. de Bono, J.; Mateo, J.; Fizazi, K.; Saad, F.; Shore, N.; Sandhu, S.; Chi, K.N.; Sartor, O.; Agarwal, N.; Olmos, D.; et al. Olaparib for Metastatic Castration-Resistant Prostate Cancer. N. Engl. J. Med. 2020, 382, 2091–2102. [Google Scholar] [CrossRef]
  10. Golan, T.; Hammel, P.; Reni, M.; Van Cutsem, E.; Macarulla, T.; Hall, M.J.; Park, J.-O.; Hochhauser, D.; Arnold, D.; Oh, D.-Y.; et al. Maintenance Olaparib for Germline BRCA-Mutated Metastatic Pancreatic Cancer. N. Engl. J. Med. 2019, 381, 317–327. [Google Scholar] [CrossRef]
  11. Kindler, H.L.; Hammel, P.; Reni, M.; Van Cutsem, E.; Macarulla, T.; Hall, M.J.; Park, J.O.; Hochhauser, D.; Arnold, D.; Oh, D.-Y.; et al. Overall Survival Results From the POLO Trial: A Phase III Study of Active Maintenance Olaparib Versus Placebo for Germline BRCA-Mutated Metastatic Pancreatic Cancer. J. Clin. Oncol. 2022, 40, 3929–3939. [Google Scholar] [CrossRef] [PubMed]
  12. Reiss, K.A.; Mick, R.; O’Hara, M.H.; Teitelbaum, U.; Karasic, T.B.; Schneider, C.; Cowden, S.; Southwell, T.; Romeo, J.; Izgur, N.; et al. Phase II Study of Maintenance Rucaparib in Patients With Platinum-Sensitive Advanced Pancreatic Cancer and a Pathogenic Germline or Somatic Variant in BRCA1, BRCA2, or PALB2. J. Clin. Oncol. 2021, 39, 2497–2505. [Google Scholar] [CrossRef]
  13. Boyle, T.A.; Mondal, A.K.; Saeed-Vafa, D.; Ananth, S.; Ahluwalia, P.; Kothapalli, R.; Chaubey, A.; Roberts, E.; Qin, D.; Magliocco, A.M.; et al. Guideline-Adherent Clinical Validation of a Comprehensive 170-Gene DNA/RNA Panel for Determination of Small Variants, Copy Number Variations, Splice Variants, and Fusions on a Next-Generation Sequencing Platform in the CLIA Setting. Front. Genet. 2021, 12, 503830. [Google Scholar] [CrossRef] [PubMed]
  14. Tung, N.M.; Robson, M.E.; Ventz, S.; Santa-Maria, C.A.; Nanda, R.; Marcom, P.K.; Shah, P.D.; Ballinger, T.J.; Yang, E.S.; Vinayak, S.; et al. TBCRC 048: Phase II Study of Olaparib for Metastatic Breast Cancer and Mutations in Homologous Recombination-Related Genes. J. Clin. Oncol. 2020, 38, 4274–4282. [Google Scholar] [CrossRef]
  15. Batalini, F.; Madison, R.W.; Sokol, E.S.; Jin, D.X.; Chen, K.T.; Decker, B.; Pavlick, D.C.; Frampton, G.M.; Wulf, G.M.; Garber, J.E.; et al. Homologous Recombination Deficiency Landscape of Breast Cancers and Real-World Effectiveness of Poly ADP-Ribose Polymerase Inhibitors in Patients With Somatic BRCA1/2, Germline PALB2, or Homologous Recombination Deficiency Signature. JCO Precis. Oncol. 2023, 7, e2300091. [Google Scholar] [CrossRef] [PubMed]
  16. Mohyuddin, G.R.; Aziz, M.; Britt, A.; Wade, L.; Sun, W.; Baranda, J.; Al-Rajabi, R.; Saeed, A.; Kasi, A. Similar response rates and survival with PARP inhibitors for patients with solid tumors harboring somatic versus Germline BRCA mutations: A Meta-analysis and systematic review. BMC Cancer 2020, 20, 507. [Google Scholar] [CrossRef]
  17. Fusco, M.J.; Saeed-Vafa, D.; Carballido, E.M.; Boyle, T.A.; Malafa, M.; Blue, K.L.; Teer, J.K.; Walko, C.M.; McLeod, H.L.; Hicks, J.K.; et al. Identification of Targetable Gene Fusions and Structural Rearrangements to Foster Precision Medicine in KRAS Wild-Type Pancreatic Cancer. JCO Precis. Oncol. 2021, 5, 65–74. [Google Scholar] [CrossRef]
  18. Philip, P.A.; Azar, I.; Xiu, J.; Hall, M.J.; Hendifar, A.E.; Lou, E.; Hwang, J.J.; Gong, J.; Feldman, R.; Ellis, M.; et al. Molecular Characterization of KRAS Wild-type Tumors in Patients with Pancreatic Adenocarcinoma. Clin. Cancer Res. 2022, 28, 2704–2714. [Google Scholar] [CrossRef]
  19. Elhariri, A.; Patel, J.; Mahadevia, H.; Albelal, D.; Ahmed, A.K.; Jones, J.C.; Borad, M.J.; Babiker, H. Identifying Actionable Alterations in KRAS Wild-Type Pancreatic Cancer. Target. Oncol. 2024, 19, 679–689. [Google Scholar] [CrossRef]
  20. Javle, M.; Shacham-Shmueli, E.; Xiao, L.; Varadhachary, G.; Halpern, N.; Fogelman, D.; Boursi, B.; Uruba, S.; Margalit, O.; Wolff, R.A.; et al. Olaparib Monotherapy for Previously Treated Pancreatic Cancer With DNA Damage Repair Genetic Alterations Other Than Germline BRCA Variants: Findings From 2 Phase 2 Nonrandomized Clinical Trials. JAMA Oncol. 2021, 7, 693–699. [Google Scholar] [CrossRef]
  21. Joris, S.; Denys, H.; Collignon, J.; Rasschaert, M.; T’Kint de Roodenbeke, D.; Duhoux, F.P.; Canon, J.-L.; Tejpar, S.; Mebis, J.; Decoster, L.; et al. Efficacy of olaparib in advanced cancers with germline or somatic mutations in BRCA1, BRCA2, CHEK2 and ATM, a Belgian Precision tumor-agnostic phase II study. ESMO Open 2023, 8, 102041. [Google Scholar] [CrossRef] [PubMed]
  22. Nakamura, K.; Hayashi, H.; Kawano, R.; Ishikawa, M.; Aimono, E.; Mizuno, T.; Kuroda, H.; Kojima, Y.; Niikura, N.; Kawanishi, A.; et al. BRCA1/2 reversion mutations in a pan-cancer cohort. Cancer Sci. 2024, 115, 635–647. [Google Scholar] [CrossRef] [PubMed]
  23. Brown, T.J.; Yablonovitch, A.; Till, J.E.; Yen, J.; Kiedrowski, L.A.; Hood, R.; O’Hara, M.H.; Teitelbaum, U.; Karasic, T.B.; Schneider, C.; et al. The Clinical Implications of Reversions in Patients with Advanced Pancreatic Cancer and Pathogenic Variants in BRCA1, BRCA2, or PALB2 after Progression on Rucaparib. Clin. Cancer Res. 2023, 29, 5207–5216. [Google Scholar] [CrossRef] [PubMed]
  24. Lin, K.K.; Harrell, M.I.; Oza, A.M.; Oaknin, A.; Ray-Coquard, I.; Tinker, A.V.; Helman, E.; Radke, M.R.; Say, C.; Vo, L.T.; et al. BRCA Reversion Mutations in Circulating Tumor DNA Predict Primary and Acquired Resistance to the PARP Inhibitor Rucaparib in High-Grade Ovarian Carcinoma. Cancer Discov. 2019, 9, 210–219. [Google Scholar] [CrossRef]
  25. Loehr, A.; Hussain, A.; Patnaik, A.; Bryce, A.H.; Castellano, D.; Font, A.; Shapiro, J.; Zhang, J.; Sautois, B.; Vogelzang, N.J.; et al. Emergence of BRCA Reversion Mutations in Patients with Metastatic Castration-resistant Prostate Cancer After Treatment with Rucaparib. Eur. Urol. 2023, 83, 200–209. [Google Scholar] [CrossRef]
  26. Mitri, Z.; Goodyear, S.M.; Mills, G. Strategies for the prevention or reversal of PARP inhibitor resistance. Expert Rev. Anticancer. Ther. 2024, 24, 959–975. [Google Scholar] [CrossRef]
  27. Kawamoto, Y.; Yamai, T.; Ikezawa, K.; Seiki, Y.; Watsuji, K.; Hirao, T.; Urabe, M.; Kai, Y.; Takada, R.; Mukai, K.; et al. Clinical significance of germline breast cancer susceptibility gene (gBRCA) testing and olaparib as maintenance therapy for patients with pancreatic cancer. BMC Cancer 2024, 24, 1000. [Google Scholar] [CrossRef]
  28. Kindler, H.L.; Yoo, H.K.; Hettle, R.; Cui, K.Y.; Joo, S.; Locker, G.Y.; Golan, T. Patient-centered outcomes in the POLO study of active maintenance olaparib for germline BRCA-mutated metastatic pancreatic cancer. Cancer 2023, 129, 1411–1418. [Google Scholar] [CrossRef]
  29. Kubo, T.; Muramatsu, J.; Arihara, Y.; Murota, A.; Ishikawa, K.; Yoshida, M.; Nagashima, H.; Tamura, F.; Ikeda, Y.; Usami, M.; et al. Clinical characterization of patients with gBRCA1/2 mutation-positive unresectable pancreatic cancer: A multicenter prospective study. Jpn J. Clin. Oncol. 2024, 54, 47–53. [Google Scholar] [CrossRef]
  30. Miao, R.; Yu, J.; Blue, K.; Sommerer, K.; Shah, A.; Bottiglieri, S.; Ho, T.; Hicks, K.; Kim, D.W. 354P PARP inhibitors in Pancreatic Cancer with Homologous Recombination Repair Gene Mutations: A Single-Institution Experience. In Proceedings of the ESMO Gastrointestinal Cancers Congress 2024, Munich, Germany, 26–29 June 2024. [Google Scholar]
Cancers 16 03447 g001
Figure 1. Kaplan–Meier curves of progression-free survival and overall survival stratified by germline vs. somatic mutation (A,B), HRR genes (C,D), and treatment setting (E,F).
Figure 1. Kaplan–Meier curves of progression-free survival and overall survival stratified by germline vs. somatic mutation (A,B), HRR genes (C,D), and treatment setting (E,F).
Cancers 16 03447 g001
Table 1. Patient characteristics.
Table 1. Patient characteristics.
Baseline CharacteristicsPatients (n = 48)
Age, years, median (range)71 (42–90)
Sex, n (%)
Male
Female
26 (54)
22 (46)
Race, n (%)
White48 (100)
ECOG at screening, n (%)
07 (15)
128 (58)
213 (27)
Site of primary tumor, n (%)
Head23 (48)
Body14 (29)
Tail11 (23)
Staging, n (%)
Locally advanced disease9 (19)
Metastatic disease39 (81)
Metastatic site, n (%)n = 39
Liver26 (67)
Lung11 (28)
Peritoneum8 (21)
Retroperitoneal lymph nodes5 (13)
HRR mutation, n (%)
Germline BRCA or PALB217 (35)
Somatic BRCA or PALB26 (13)
Germline non-BRCA non-PALB2 HRR19 (40)
Somatic non-BRCA non-PALB2 HRR12 (25)
RAS status, n (%)
Wild type11 (23)
KRAS G12D6 (13)
KRAS G12R3 (6)
KRAS G12S1 (2)
KRAS G12V9 (19)
KRAS Q61H3 (6)
NRAS G12D1 (2)
Unknown14 (29)
Treatment setting, n (%)
First-line monotherapy5 (10)
First-line maintenance therapy 32 (74)
Subsequent line maintenance therapy11 (26)
Previous chemotherapy, n (%)n = 43
FOLFIRINOX25 (58)
Gemcitabine/nab-paclitaxel21 (49)
Gemcitabine/cisplatin3 (7)
5FU/liposomal irinotecan3 (7)
FOLFOX2 (5)
Liposomal irinotecan monotherapy1 (2)
Gemcitabine monotherapy1 (2)
Other (trametinib, cobimetinib)1 (2)
ECOG, Eastern Cooperative Oncology Group. HRR, homologous recombination repair.
Table 2. Best overall response by HRR gene mutation.
Table 2. Best overall response by HRR gene mutation.
Best Overall ResponseTotal
Evaluable		Germline BRCA or PALB2 *Somatic BRCA or PALB2 *Germline
Non-BRCA Non-PALB2 HRR *		Somatic Non-BRCA Non-PALB2 HRR *Germline
and Somatic HRR #		p Value
n = 46n = 14n = 3n = 14n = 9n= 6
PR, n (%)10 (22)4 (29)1 (33) 1 (11)4 (67)
SD, n (%)26 (57)7 (50)2 (67)12 (86)3 (33)2 (33)
PD, n (%)10 (22)3 (21) 2 (14)5 (56)
ORR (CR + PR), n (%)10 (22)4 (29)1 (33)0 (0)1 (11)4 (67)0.016
DCR (CR + PR + SD), n (%)36 (78)11 (79)3 (100)12 (86)4 (44)6 (100)0.061
* Excluding patients with concomitant germline and somatic HRR mutations. # Patients with concomitant germline and somatic HRR mutations. CR, complete response. PR, partial response. SD, stable disease. PD, progressive disease. ORR, objective response rate. DCR, disease control rate.
Table 3. Survival estimates.
Table 3. Survival estimates.
Progression-Free Survival (Months)Overall Survival (Months)
nMedian95% CILog-Rank pMedian95% CILog-Rank p
All 486.93.4–10.4 11.56.0–17.0
HRR mutation
BRCA/PALB2219.45.6–13.20.66211.55.8–17.20.665
Non-BRCA/PALB2275.93.5–8.3 14.45.4–23.4
Germline mutation *308.34.0–12.60.02514.05.7–22.30.101
Somatic mutation *123.00.0–6.4 6.85.4–8.2
Concomitant germline and somatic #610.23.2–17.2 11.50.0–24.3
Germline BRCA/PALB2 *146.10.0–12.5<0.0018.62.7–14.50.121
Somatic BRCA/PALB2 *312.2 16.2
Germline non-BRCA/PALB2 *168.30.0–16.8 17.612.6–22.6
Somatic non-BRCA/PALB2 *92.62.5–2.7 5.94.0–7.8
Concomitant germline and somatic #610.23.2–17.2 11.50.0–24.3
Treatment setting
Maintenance436.93.6–10.20.60811.54.3–18.70.629
First line511.30.0–25.7 11.31.6–21.0
Chemotherapy prior to maintenance
Platinum based255.10.7–9.50.15414.04.2–23.80.919
Non-platinum based1810.22.5–17.9 11.53.5–19.5
* Excluding patients with concomitant germline and somatic HRR mutations. # Patients with concomitant germline and somatic HRR mutations.
Table 4. Performance status and best overall response by treatment setting of PARP inhibitors.
Table 4. Performance status and best overall response by treatment setting of PARP inhibitors.
TotalMaintenance
after Platinum		Maintenance
after Non-Platinum		First Line
ECOGn = 48n = 25n = 18n = 5
0, n (%)7 (15)7 (28)0 (0)0 (0)
1, n (%)28 (58)17 (68)11 (61)0 (0)
2, n (%)13 (27)1 (4)7 (39)5 (100)
Best overall responseEvaluable n = 46n = 24n = 17n = 5
PR, n (%)10 (22)3 (13)6 (35)1 (20)
SD, n (%)26 (57)13 (54)9 (53)4 (80)
PD, n (%)10 (22)8 (33)2 (12)
ORR (CR + PR), n (%)10 (22)3 (13)6 (35)1 (20)
DCR (CR + PR + SD), n (%)36 (78)16 (67)15 (88)5 (100)
ECOG, Eastern Cooperative Oncology Group. CR, complete response. PR, partial response. SD, stable disease. PD, progressive disease. ORR, objective response rate. DCR, disease control rate.
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

Miao, R.; Blue, K.; Sommerer, K.; Shah, A.; Bottiglieri, S.; del Cueto, A.; Berry, D.K.; Ho, T.T.; Hicks, J.K.; Kim, D.W. PARP Inhibitors in Pancreatic Cancer with Homologous Recombination Repair Gene Mutations: A Single-Institution Experience. Cancers 2024, 16, 3447. https://doi.org/10.3390/cancers16203447

AMA Style

Miao R, Blue K, Sommerer K, Shah A, Bottiglieri S, del Cueto A, Berry DK, Ho TT, Hicks JK, Kim DW. PARP Inhibitors in Pancreatic Cancer with Homologous Recombination Repair Gene Mutations: A Single-Institution Experience. Cancers. 2024; 16(20):3447. https://doi.org/10.3390/cancers16203447

Chicago/Turabian Style

Miao, Ruoyu, Kirsten Blue, Katelyn Sommerer, Anand Shah, Sal Bottiglieri, Alex del Cueto, Darcy K. Berry, Teresa T. Ho, James Kevin Hicks, and Dae Won Kim. 2024. "PARP Inhibitors in Pancreatic Cancer with Homologous Recombination Repair Gene Mutations: A Single-Institution Experience" Cancers 16, no. 20: 3447. https://doi.org/10.3390/cancers16203447

APA Style

Miao, R., Blue, K., Sommerer, K., Shah, A., Bottiglieri, S., del Cueto, A., Berry, D. K., Ho, T. T., Hicks, J. K., & Kim, D. W. (2024). PARP Inhibitors in Pancreatic Cancer with Homologous Recombination Repair Gene Mutations: A Single-Institution Experience. Cancers, 16(20), 3447. https://doi.org/10.3390/cancers16203447

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop