Multimodality therapy in metastatic pancreas cancer with a BRCA mutation and durable long-term outcome: biology, intervention, or both?

ABSTRACT

Metastatic pancreatic adenocarcinoma (PDAC) is a rapidly lethal disease, with less than half of patients surviving 12 months, and 5-year survival approximately 3%. These outcomes are in large part due to a lack of effective medical and surgical therapies for metastatic PDAC. Herein, we present the case of a patient with oligometastatic liver recurrence of BRCA2-mutated PDAC following a curative-intent resection. Through a combination of systemic chemotherapy, metastasectomy, radiotherapy, and subsequent targeted therapy with olaparib, the patient is asymptomatic four years following metastatic diagnosis with stable low-volume disease. This patient’s excellent outcome is attributable to the multi-disciplinary care received, all aspects of which were informed by new evidence surrounding metastasectomy for metastatic PDAC, the unique biology and medical treatment of BRCA-mutated PDAC, and the role of radiotherapy in controlling locoregional recurrence. We provide a review of this evidence, while highlighting the importance of evaluating disease biology through somatic and germline genetic testing as well as monitoring response to systemic chemotherapy.

KEYWORDS:

• Pancreatic adenocarcinoma
• BRCA2
• olaparib
• metastasectomy
• radiotherapy
• long-term survival
• cancer biology
• complete radiographic response

Introduction

Metastatic pancreatic adenocarcinoma (PDAC) is a rapidly lethal disease. Poor outcomes are in large part due to a lack of effective medical and surgical therapies in the setting of metastatic disease. To effectively for patients with metastatic PDAC, a patient-specific understanding of disease biology and potential sensitivities to novel therapeutics is a necessity. Herein, we present the case of a patient with oligometastatic liver recurrence of BRCA2-mutated PDAC with long-term disease control through a combination of surgical, medical, and radiotherapy; these interventions were made possible through insights into the patient’s biology, which allowed tailored evidence-based interventions to alter disease trajectory. The principles guiding the management in this case are instructive, and reflect the future treatment landscape of patients with this malignancy as we discover novel therapeutics and novel indications for interventional therapies.

Case report

JT is a 56-year-old male with no significant past medical, family, or surgical history who was identified to have a 5 cm pancreatic tail mass on imaging performed for vague abdominal discomfort (Figure 1a). He underwent endoscopic fine needle aspiration, with cytology consistent with pancreatic ductal adenocarcinoma (PDAC). A subsequent staging computed tomography (CT) chest, abdomen, and pelvis demonstrated no evidence of distant metastatic disease. CA 19–9 at diagnosis was 4.0 U/ml. He underwent diagnostic laparoscopy, which was negative for peritoneal disease, followed by an antegrade modular pancreatosplenectomy (RAMPS) procedure. Pathology demonstrated a 6 cm, node negative (N0), margin negative (R0) pancreas ductal adenocarcinoma with perineural and lymphovascular invasion. American Joint Commission on Cancer (AJCC) 8^th edition stage was pT3N0, stage IIA.

Figure 1. Selected Computed Tomography (CT) Imaging at Clinically Important Timepoints. a) CT at time of diagnosis showing 5 cm distal pancreatic mass. b) CT following four months of adjuvant gemcitabine/capecitabine demonstrating a 1 cm segment V liver metastasis c) CT following three months of FOLFIRINOX showing complete radiographic response of segment V liver metastasis. d) CT two years following metastasectomy demonstrating a 4 cm caudate lobe recurrence

He received four months of adjuvant gemcitabine and capecitabine per the European Study Group for Pancreatic Cancer (ESPAC)-4 trial,¹ the standard of care at the time. Per institutional practice for margin-negative resections, he was not given adjuvant radiotherapy. A 1 cm segment V liver lesion was noted on CT prior to completion of planned therapy (Figure 1b). CA 19–9 was 2.0 U/ml. Contrast-enhanced magnetic resonance imaging confirmed a solitary segment V lesion with restricted diffusion and was negative for other sites of metastatic disease. His regimen was changed to 5-fluorouracil, oxaliplatin, irinotecan, and folinic acid (FOLFIRINOX), which he received for three months. On restaging, his liver metastasis had resolved (Figure 1c). He was taken to the operating room for an intraoperative ultrasound of the liver, which confirmed a small residual area of abnormal echotexture in segment V with no other sites of intrahepatic disease. He underwent wedge resection of the lesion, with pathology demonstrating a small focus of residual adenocarcinoma. Margins were negative. No adjuvant therapy was administered.

The patient was surveilled with CT of the chest, abdomen, and pelvis and serial CA 19–9 measurements every 3 months; he remained asymptomatic and without biochemical or radiographic evidence of disease until 2 years following his hepatectomy (31 months following RAMPS), when imaging revealed a new 4 cm caudate lobe mass with enhancing soft tissue in the pancreatic resection bed and at the celiac trunk, suspicious for locoregional recurrence (Figure 1d). CA 19–9 was 6.5 U/ml. Percutaneous biopsy of the caudate lesion confirmed adenocarcinoma consistent with pancreatic origin. Next-generation tumor sequencing (GeneTrails® Comprehensive Solid Tumor Panel, Knight Diagnostic Laboratory, Portland, OR) was performed, which revealed a tumor mutational burden of 9.8 mutations per megabase, a KRAS G12V mutation, and an BRCA2 frameshift mutation (p.E1646fs*23). Germline genetic testing revealed an identical BRCA2 frameshift mutation. The patient received FOLFIRINOX for 4 months, followed by ablative hypofractionated radiotherapy to 67.5 Gy over 15 fractions with a partial radiographic response. He was subsequently initiated on olaparib maintenance therapy, and experienced continued progressive shrinkage of his caudate lesion over 12 months on therapy, with stability of the likely locoregional recurrence. He is currently 4 years from his initial diagnosis of metastatic PDAC (55 months from his initial RAMPS) and remains asymptomatic on olaparib. The patient gave consent for the publication of this case report.

Literature review/discussion

Metastatic PDAC is almost universally a lethal condition, with one-year overall survival (OS) of less than 15%, and approximately 3% 5-year OS.^2–4 Metastasectomy series for oligometastatic PDAC have previously been reported, however prior to 2016 there were no studies showing a survival benefit or demonstrating improved outcomes compared to most patients with metastatic PDAC.^5–9 In 2016, Tachezy and colleagues reported that simultaneous liver resection and pancreatectomy resulted in improved survival in patients with oligometastatic liver disease identified at the time of planned curative-intent resection.¹⁰ However, patients undergoing simultaneous resection still had poor OS, with a median OS of 13.6 versus 7 months in the group with aborted resections. In 2017, Frigerio and colleagues reported in a review that a subset of patients with oligometastatic liver disease that resolved following chemotherapy and had normalized CA 19–9 levels were able to undergo resection with median recurrence-free survival of 27 months and median OS of 56 months.¹¹ While this group represented approximately 5% of all patients with metastatic PDAC during the study interval, this finding nonetheless represented the first subset of patients with metastatic disease who may have derived benefit from surgical intervention. Importantly, however, the question of whether the observed benefit reflects disease biology or an independent impact of intervention could not be answered.

Worthy of additional discussion are patients with lung-only oligometastatic disease; this is a rare clinical entity, however, it is the most frequent recurrence pattern in patients who develop recurrent disease after three years from diagnosis.^12,13 This group is thought to have less aggressive disease than patients with other patterns of metastatic spread. Yasukawa and colleagues recently demonstrated that resection of oligometastatic disease in such patients resulted in an overall survival of 47 months.¹⁴ Similar findings were reported in smaller series by Arnaoutakis et al. and Tagawa et al.^15,16 Given the relatively excellent prognosis of this group at baseline, these findings again beg the question of whether these outcomes are due to disease biology or an effect from resection.

The biology of BRCA-mutated PDAC is instructive, as tumors initiate from mutations due to deficient homologous recombination DNA damage repair (HR-DDR) of single strand DNA breaks, in which the BRCA genes are intimately involved. Indeed, in the Know Your Tumor program of the Pancreatic Cancer Action Network (PanCAN), 16.5% of 820 sequenced patients with PDAC had somatic or germline mutations involved in the HR-DDR pathway, most commonly BRCA1/2 in 5–7% of cases.^17,18 This is clinically relevant, as patients with BRCA-deficient PDAC have improved clinical outcomes compared to BRCA-intact PDAC, especially when treated with platinum-containing regimens.^19,20 This phenomenon is due to HR-DDR-mediated repair of platinum-induced DNA damage in HR-DDR-intact tumors.²¹ The implications for clinical practice indicate routine genetic testing in all patients with PDAC as recommended by the American Society of Clinical Oncology and National Comprehensive Cancer Network;^22,23 additionally, ATM, PALB2, MLH1, MSH2/6, PMS2, CDKN2A, and TP53 mutations have been identified in PDAC and may lead to additional targeted therapies or other treatment possibilities in the future.²⁴ For instance, patients with high microsatellite instability (MSI-H) due to mutations in MLH1, MSH2/6, and PMS2 may benefit from immune checkpoint inhibition with pembrolizumab.^25,26 To date, however, pembrolizumab is not well studied specific in patients with MSI-H PDAC.

In patients with HR-DDR-deficient tumors, olaparib functions by inhibiting the poly (ADP-ribose) polymerase (PARP) family of proteins, which has many functions including repair of single-stranded DNA breaks that arise during replication.²⁷ In cancers with otherwise intact DNA repair mechanisms, olaparib has not demonstrated efficacy, however in cancers with deficient HR-DDR such as BRCA-mutated PDAC, olaparib is tumoricidal via inducing DNA damage and programmed cell death.^27–29 In BRCA-mutated tumors, this effect is unchanged whether the mutation is somatic versus germline; and in our patient biallelic loss was identified likely underscoring the response.^30,31 In the landmark study by Golan and colleagues, olaparib in patients with BRCA-mutated PDAC with stable or responding disease following 4 months of FOLFIRINOX led to an improvement in progression-free survival (7.4 vs 3.8 months; hazard ratio 0.53; 95% CI 0.35–0.82; P = .004), but not OS (18.9 vs 18.1 months; hazard ratio 0.91; 95% CI, 0.56 to 1.46; P = .68).³² Similar benefits have been noted for PARP inhibitors in other treatment settings,³³ this includes patients with “BRCAness,” or HR-DDR-deficiency in the absence of a BRCA mutation.³⁴

Ultimately, the development of PARP-inhibitor resistance leads to disease progression; known escape mechanisms include somatic reversion mutations in BRCA1/2 that restore wild-type gene function, and can occur in somatic or germline BRCA mutations.^35,36 BRCA1/2 reversion mutations are induced by platinum agents, however whether PARP inhibition has a similar effect remains unknown. Compensatory mutations in downstream HR-DDR genes (53BP1, RIF1, PTIP, REV7) can also restore HR-DDR independent of BRCA.^37–41 Hypermethylation of BRCA1/2 genes has also been hypothesized as a mechanism of resistance, but is less well characterized and contribution in PDAC is unknown.⁴² Regardless, identifying and overcoming olaparib resistance mechanisms presents a future target for furthering the care of patients with metastatic BRCA-mutated PDAC.

A final point of consideration is whether the patient’s sustained local control is due to olaparib, radiotherapy, and/or a contribution from underlying biology. A recent study of patients with locally advanced PDAC by Reyngold and colleagues demonstrated a 12 and 24-month rate of locoregional progression of 17.6% (95% CI, 10.4%–24.9%) and 32.8% (95% CI, 21.6%–44.1%), respectively, with the use of hypofractionated ablative radiotherapy.⁴³ Thus, while the patient’s continued distant control is attributable to olaparib, whether a synergistic effect of olaparib and radiotherapy exists is unclear.

The studies discussed herein have several notable limitations. Firstly, the metastasectomy trials are universally retrospective and nonrandomized, with a high risk of selection bias. Therefore, their results cannot be attributed to an independent effect of surgical intervention in these patients, especially as genetic data that may indicate more favorable biology is not available in such studies. Additionally, much is left to discover on the genetic underpinnings of pancreatic cancer, and how various driver mutations may interact with current and future chemotherapeutics and targeted therapies.

In conclusion, the present case exemplifies the excellent outcomes that can be achieved with multidisciplinary surgical, medical, and radiotherapy in small subset of patients with metastatic PDAC; such outcomes are only possible when treatment is informed by underlying disease biology through germline and somatic testing and observing disease response to systemic therapy. Metastasectomy can be performed with excellent long-term results in selected patients with oligometastatic disease isolated to either the liver or lungs, and at the very least allows for an extended period off-treatment in such patients, if not an independent survival benefit. We believe this case report is instructive to emphasize the necessity of multidisciplinary care and comprehensive genomic testing in PDAC.

Declarations of Interest

Dr. O’Reilly benefits from research funding to Memorial Sloan Kettering from Genentech/Roche, Celgene/BMS, BioNTech, BioAtla, AstraZeneca, Arcus, Elicio, Parker Institute, and AstraZeneca. Dr. O’Reilly has a consulting role with the following companies: Cytomx Therapeutics (DSMB), Rafael Therapeutics (DSMB), Sobi, Silenseed, Tyme, Seagen, Molecular Templates, Boehringer Ingelheim, BioNTech, Ipsen, Polaris, Merck, IDEAYA, Cend, AstraZeneca, Noxxon, BioSapien, Bayer (spouse), Genentech-Roche (spouse), Celgene-BMS (spouse), Eisai (spouse). The other authors have no potential conflicts of interest to disclose.

Presentation

This work was presented at the National Pancreatic Foundation Fellow’s Symposium in May 2021.

Acknowledgments

The authors thank Aasheesh Kanwar, MD for assistance with figure preparation.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.