Dramatic, durable response to therapy in gBRCA2-mutated pancreas neuroendocrine carcinoma: opportunity and challenge – npj Precision Oncology

The first-line treatment of PDNECs has traditionally followed that of small cell lung cancer, with best evidence supporting the use of cisplatin and etoposide^10,11. A diagnosis of PDNEC portends a poor prognosis, with a median survival of 5.7 months¹². The incorporation of a maintenance phase of therapy into treatment paradigms is a subject of investigation across cancer types and is aimed to maintain and/or induce disease regression, while typically allowing de-escalation or removal of cytotoxic therapy to reduce toxicity and maximize QoL. Notable, relevant examples pertinent to this case are in the setting of extensive stage small cell lung cancer, where international guidelines incorporate immune checkpoint inhibitors, atezolizumab or durvalumab, in combination with chemotherapy, followed by maintenance checkpoint blockade without cytotoxic therapy until disease progression, based on two FDA approvals¹³. Additionally, the phase III Pancreas Olaparib Ongoing (POLO) trial elucidated a biomarker driven approach to the treatment of advanced pancreas ductal adenocarcinoma (PDAC) and marked a potential new era of precision medicine for this disease⁴ with a progression free survival advantage over placebo observed for maintenance olaparib in patients with germline BRCA1/2 mutated PDAC and platinum-sensitive disease. Benefits have been observed across tumor types, including ovarian⁵, breast^6,7 and prostate cancer⁸, leading to regulatory approvals of PARPis in these diseases.

Somatic BRCA2 LOH was detected in the tumor samples from this patient. Previous work from our group has indicated that in PDAC, patients with biallelic alterations affecting homologous recombination DNA repair-related genes (e.g., BRCA1/2) are the most likely to benefit from platinum-based therapy^14,15 and PARPi therapy¹⁴, with often durable responses. Those with biallelic status, such as described herein, are associated with a higher TMB, and display a COSMIC Signature 3, which are indicators of greater genomic instability, and postulated to be more likely to benefit from immunotherapy^16,17 in the context of BRCA2 alterations¹⁸. In view of the excellent response to platinum-based chemotherapy, and extrapolating from the above data with a goal to personalize treatment recommendations, we opted to proceed with maintenance PARPi therapy, which resulted in a prolonged period of systemic disease control. Given the initial dramatic response to platinum-based chemotherapy (and immunotherapy) observed, it is possible that the disease responses identified on subsequent imaging were due entirely to ongoing, exceptional response to chemotherapy, and not secondary to olaparib. A recent series from Symonds et al.¹⁹ demonstrated remarkable disease control with olaparib in a patient with de novo PDNEC of the prostate with BRCA2 loss, again in the post-platinum chemotherapy setting. In our case, as in most scenarios, the commencement of PARPi was the setting of disease response to platinum-based therapy, thus definitively determining which agent has resulted in disease response and control, can prove challenging.

The case herein demonstrates significant benefits arising from results of genomic testing for this patient. Current international guidelines including the National Comprehensive Cancer Network (NCCN) guidelines, recommend that genetic counseling and testing for inherited genetic conditions should be considered, but do not recommend universal genomic testing for all patients with neuroendocrine tumors, including PDNEC¹⁷. While data pertaining to comprehensive genomic sequencing in pancreatic NECs has traditionally been sparse, a number of recent series have demonstrated enrichment for alterations in TP53, RB1, APC, KRAS, BRAF^18,19, copy number losses in ARID1A, ATM and ESR1, in addition to amplifications/gains in MYC and KDM5A¹⁹. Recent studies in both pancreatic and non-pancreatic gastrointestinal NECs have demonstrated the presence of potentially actionable alterations^19,20. Specific to BRCA alterations, one series demonstrated that 25% of patients with neuroendocrine cancer of the prostate had detectable biallelic BRCA2 alterations¹⁶, underpinning a critical need to recommend genomic testing to detect potentially actionable targets and is applicable across solid tumor types. Given this data, as well as data in BRCA mutated pancreatic adenocarcinoma demonstrating the predictive implications of biallelic status¹⁴, in the setting of the identification of a somatic BRCA alteration we would suggest consideration of both reflexive germline testing as well as adjudication of biallelic/monoallelic status. The potential of comprehensive genomic testing to offer meaningful therapeutic benefits to patients may be underappreciated in the context of rare cancer types, where a paucity of genomic characterization has been conducted.

While the initial rationale behind the use of atezolizumab in this case was based on extrapolation from the survival data in small cell lung cancer⁸, the presence of the BRCA2 alteration further supported its use. In our previous series of patients with PDAC and mutations in genes associated with homologous recombination deficiency (HRd) e.g. BRCA 1/2, those with biallelic status such as described herein, were associated with a higher TMB compared with patients with monoallelic status, or HRd wildtype status, and additionally display a COSMIC Signature 3, indicating greater genomic instability, and postulated to be more likely to benefit from immunotherapy^21,22 in the context of BRCA2 alterations²³. In this instance, due to the limited genomic area covered in MSK-IMPACT targeted panel sequencing there were an insufficient number single nucleotide variants to compute single base substitution COSMIC mutational signatures. The optimal TMB at which immune checkpoint blockade is of benefit in neuroendocrine tumors remains an open question in the absence of randomized data, however FDA approval for the use pembrolizumab for tumors with TMB > 10 mutations per megabase (Muts/Mb) based on KEYNOTE-158 did include patients with metastatic neuroendocrine tumors²⁴. In the case described herein, a TMB of 6.2 Muts/Mb was observed.

At 22 months from diagnosis, our patient developed symptomatic intracranial disease involvement, and despite best efforts with multi-modality approaches, intracranial disease control was not achieved. Prophylactic cranial irradiation (PCI) is not routinely recommended in major international guidelines for extra-pulmonary neuroendocrine carcinomas, in contrast to extensive stage small cell lung cancer, where PCI is considered based on an EORTC trial which demonstrated a survival advantage²⁵. Our case is reflective of the challenge of intracranial disease progression, which can limit survival in patients with otherwise excellent systemic disease control. In the absence of randomized data, our case raises the question of whether PCI should be considered in select patients in whom systemic disease control is maintained.

Multiple potential causative factors may have led to the development of CNS metastases in this case, and merit pause for consideration. First, in this case a baseline imaging study of the central nervous system to assess for the presence of brain metastases was not performed, thus it is possible that occult brain metastases were present at the time of diagnosis, although no intracranial abnormality was noted on MRI Brain six months following diagnosis. Second, the presence of BRCA mutations is associated with a higher prevalence of CNS metastases in breast and ovarian cancers²⁶, although this may be accounted for by several potential factors, including enrichment of triple-negative subtype in BRCA-driven breast cancers, as well as favorable survival in these subgroups. Data pertaining to whether a biological predisposition to CNS pattern of metastasis in BRCA-mutated pancreatic cancer is lacking. Third, while PARPi have resulted in CNS activity in some pre-clinical models²⁷, other studies have shown suboptimal ability of the PARPis rucaparib and talazoparib to cross the blood brain barrier^28,29. This is thought to be in part due to presence of P-glycoprotein (P-GP/ABCB1) and Breast Cancer Resistance Protein (BCRP) which function as efflux pumps at the blood brain barrier and limit CNS penetration. Olaparib is also a substrate of these proteins³⁰ and therefore the CNS may represent a sanctuary site in this setting. Fourth, and perhaps the most parsimonious conclusion for this patient, the development of a CNS metastasis after 22 months of sustained disease control is best accounted for by the development of a reversion mutation (BRCA2 rearrangement: c.316 + 1367 c.717del, Figs. 3 and 4).

The development of reversion mutations to targeted therapy, including specifically in BRCA1/2, leading to resistance to the PARPi, have been described^31,32, albeit not, to our knowledge, in the setting of isolated CNS disease with ongoing excellent systemic control^{33,34,35,36,37}. Overcoming resistance to targeted therapy remains a formidable challenge. The addition of immunotherapy to PARPi therapy is under investigation in several malignancies (NCT04548752, NCT04493060, NCT0466740), with benefit observed, as a potential combination to address resistance^38,39. In addition, the combination PARPis with DNA polymerase θ (Polθ, also known as POLQ) inhibitors⁴⁰ and ataxia telangiectasia and Rad3-related (ATR) inhibitors⁴¹ may constitute a strategy to overcome resistance caused by reversion mutations.

In conclusion, here we report a unique case of a patient with a PDNEC and a BRCA2 germline mutation who had a dramatic response to platinum-based chemotherapy, followed by a period of deep, durable disease control with a PARPi, and complicated ultimately by a late intracranial relapse owing to a reversion mutation. We describe how extensive tumor sequencing uncovered that the intracranial relapse likely resulted from the development of a reversion mutation in the setting of prolonged PARPi use. This case highlights the value of a precision therapy approach which can lead to uniquely favorable outcomes for select patients, and in this regard supports the consideration of comprehensive genomic profiling, including in the management of patients with rare tumor types, where guidelines do not necessarily recommend universal genomic testing. It also re-enforces that in rare malignancies, where there is a dearth of randomized data, extrapolating from treatment paradigms for other malignancies with shared genomic features, should be entertained. Baseline CNS imaging to assess for the presence of intracranial metastases, as well as PCI should be considered in the setting of systemic disease control for PDNEC. Finally, this case provides direct evidence for the value of sequential genomic analyses at the time of disease progression on targeted therapies, to evaluate mechanisms of resistance.