A Case of a Pathological Complete Response to Neoadjuvant Nivolumab plus Ipilimumab in Periampullary Adenocarcinoma

Abstract

Herein, we report on a patient with known Lynch syndrome and periampullary adenocarcinoma that exhibited a pathological complete response to neoadjuvant nivolumab plus ipilimumab. Two MSH2 mutations, high microsatellite instability, high tumor mutational burden, and elevated PD‐L1 expression were identified by next‐generation sequencing and immunohistochemistry. Following FOLFIRINOX (Fluorouracil/Leucovorin/Irinotecan/Oxaliplatin) administration and disease progression, nivolumab (1 mg/kg) and ipilimumab (3 mg/kg) were administered every 3 weeks for four total cycles. The patient responded well with minimal adverse effects and significant improvement in epigastric pain, appetite, and body weight. She then underwent resection consisting of pancreaticoduodenectomy, which demonstrated pathological complete response. Complete genomic profiling of periampullary carcinomas is crucial for optimal treatment selection as true ampullary masses and pancreatic ductal adenocarcinoma have different genetic profiles. This case provides an example of a patient who may have further benefited from first‐line nivolumab plus ipilimumab to avoid the reduced efficacy and significant side effects associated with chemotherapy.

Key Points

• A patient with known Lynch syndrome and ampullary adenocarcinoma harboring two MSH2 mutations, high microsatellite instability (MSI‐high), high tumor mutational burden (TMB), and elevated PD‐L1 expression achieved pathological complete response with neoadjuvant nivolumab plus ipilimumab.

• The combination of nivolumab plus ipilimumab may be a better first‐line option for patients with ampullary adenocarcinomas harboring deficient mismatch repair, MSI‐high, and high TMB.

• Complete genomic profiling of periampullary adenocarcinomas is crucial for optimal treatment selection as true ampullary masses and pancreatic ductal adenocarcinoma have different genetic profiles.

• The presence of either MSI‐high or high TMB could be an appropriate predictive biomarker for response to nivolumab plus ipilimumab in the context of Lynch syndrome.

Short abstract

This article reports the case of a patient with Lynch syndrome and periampullary adenocarcinoma, providing an example of a patient who may have benefited from first‐line nivolumab plus ipilimumab to avoid the reduced efficacy and significant side effects associated with chemotherapy.

Introduction

Periampullary tumors arise within tissues near the confluence of the common bile duct with the main pancreatic duct, (i.e., the ampulla of Vater) [1]. These tumors have many different origins, with 60% arising from the pancreatic head, 20% from the ampulla of Vater, 10% from the distal common bile duct, and 10% from the duodenum [1]. It is often difficult to distinguish these cancer types using pretreatment needle biopsies. True ampullary carcinomas are defined as carcinomas arising from the ampullary complex, distal to the confluence of the common bile duct and pancreatic duct, and are rare [2]. Most periampullary carcinomas are adenocarcinomas, and there are two distinct histologic subtypes: intestinal and pancreaticobiliary [3]. These subtypes differ in biologic behavior, with the pancreaticobiliary subtype having significantly worse outcomes [4].

The pancreaticobiliary subtype is morphologically similar to pancreatic ductal adenocarcinoma (PDAC) [5] and systemic and surgical treatments are usually the same in these two tumor types. Prior to surgery, it is difficult to determine, by imaging alone, if a tumor is PDAC, ampullary carcinoma, or cholangiocarcinoma. Final surgical pathology is usually the only way to definitively differentiate between periampullary masses.

Unique aspects of the genetics of ampullary adenocarcinomas compared with PDAC could provide targets to optimize treatment. Compared with PDAC, where rates of microsatellite instability (MSI) are very low (≤1%) [6], ampullary adenocarcinomas are more likely to be MSI‐high, with prevalence ranging from 3% to 22% [7, 8, 9]. The infrequency of these tumors, variable microsatellite marker usage, and misclassification of tumor type contribute to the wide range of prevalence estimates [9]. However, strong evidence suggests MSI‐high is relatively common, and therefore, these tumors will more often be candidates for therapy targeting PD‐1 and CTLA‐4. Additionally, although most PDAC and periampullary adenocarcinomas are sporadic, data suggest up to 10% of PDAC may be due to an inherited predisposition [10]. Patients with Lynch syndrome or hereditary nonpolyposis colorectal carcinoma (HNPCC) have a significantly increased risk for developing pancreatic cancer [10]. Lynch syndrome is characterized by germline mutations in DNA mismatch repair (MMR) genes (MSH2, MLH1, MSH6, and PMS2), which leads to deficient MMR (dMMR) and MSI‐high. Therefore, patients who develop ampullary carcinoma on the background of Lynch syndrome are likely good candidates for T‐cell–modulating therapy. In this report, we describe a case that exemplifies this type of patient, where neoadjuvant immunotherapy with combined nivolumab plus ipilimumab achieved a pathological complete response in a periampullary adenocarcinoma.

Patient Story

A 59‐year‐old woman with known history of Lynch syndrome, remote history of stage IIC ovarian cancer, and colon cancer presented with back pain, pruritis, worsening fatigue, and epigastric pain. In her 30s, she underwent colectomy without adjuvant chemotherapy to treat colon cancer. At age 45, she underwent total abdominal hysterectomy with bilateral salpingo‐oophorectomy to treat ovarian cancer. Both cancers remained in remission at presentation.

A computed tomography (CT) scan of the abdomen and pelvis with contrast revealed biliary obstruction with suspected pancreatic head mass. A subsequent upper endoscopy with endoscopic ultrasound (EUS) demonstrated a 4.5‐cm periampullary mass. Endoscopic retrograde cholangiopancreatography with biopsy was performed, and a fully covered metal stent was placed. Pathology demonstrated a moderately differentiated adenocarcinoma infiltrating the duodenal submucosa. Immunohistochemistry (IHC) showed tumor cells were negative for synaptophysin, chromogranin, and PAX‐8, ruling out neuroendocrine origin and metastasis from an ovarian primary tumor. IHC also revealed loss of nuclear expression of MSH2 and MSH6. Biopsy samples were immediately sent for comprehensive genomic profiling to inform first‐line treatment selection in the context of Lynch syndrome. Based on pathology, EUS findings, and multidisciplinary tumor board discussion, the tumor was concluded to be a direct extension from an ampullary primary tumor into the duodenum.

A pretreatment abdominal and pelvis CT scan with contrast showed an ill‐defined 1.5 × 2.7‐cm ampullary mass with an adjacent 2.7 × 3.1‐cm centrally hypoattenuating lymph node, corresponding to the biopsy‐proven ampullary adenocarcinoma. The enlarged lymph node was consistent with a metastatic foramen of Winslow lymph node and was abutting the inferior vena cava (IVC). The celiac and superior mesenteric arteries and their branch vessels were remote from the masses. There was no evidence of distant metastasis. The mass was determined to be a borderline resectable tumor owing to IVC abutment, regional nodal involvement, elevated CEA (27 ng/mL), and normal CA 19‐9 (15.9 units/mL). Therefore, treatment with chemotherapy, followed by restaging, was recommended.

Based on genetic characteristics of the tumor, which will later be discussed in detail, treatment with immune checkpoint inhibitors was recommended. However, because of the insurance company's denial of this request, FOLFIRINOX (Fluorouracil/Leucovorin/Irinotecan/Oxaliplatin) was administered every 14 days for four cycles with plans to evaluate response with CT after treatment. During treatment, the patient was hospitalized for neutropenia and fever, Neupogen and intravenous antibiotics were administered, and FOLFIRINOX dose reduction was required. After four cycles of FOLFIRINOX, an abdomen and pelvis CT with contrast revealed disease progression. There was substantial increase in size of the ampullary mass to 7.5 cm in the largest dimension with worsening compression and likely encasement of the IVC (Fig. 1A). Also, there was nodular extension of tumor into the transverse mesocolon abutting the right colic vein and CEA was further elevated to 44.17 ng/mL.

Figure 1.

Computed tomography images before (A) and after (B) immunotherapy showing the periampullary mass with respect to the superior mesenteric vein (*), superior mesenteric artery (#), and inferior vena cava (&). Of note, the solid tumor component decreased in size with cystic degeneration consistent with the treatment response noted on pathology.

Molecular Tumor Board

Before first‐line treatment selection, formalin‐fixed, paraffin‐embedded tissue was sent to Foundation Medicine, Inc., based in Cambridge, Massachusetts, for comprehensive genomic profiling using the FoundationOne®CDx (F1CDx) platform (Table 1) [11]. F1CDx is a next‐generation sequencing–based diagnostic device for detection of substitutions, insertion and deletion alterations (indels), and copy number alternations in 324 genes and select gene rearrangements, as well as genomic signatures including MSI and tumor mutational burden (TMB) [12]. These results, specifically MSI and TMB, were discussed by the multidisciplinary tumor board and immune checkpoint blockers were recommended. However, this was denied by the insurance company. After disease progression with FOLFIRINOX, the medical oncologist immediately filed a request with the insurance company for approval of nivolumab plus ipilimumab. We will discuss the pertinent findings from genomic analysis, highlighting the rationale for recommending first‐line nivolumab plus ipilimumab.

Table 1.

Comprehensive genomic profiling results

Biomarkers	Results
NGS
ACVR1B	G224fs*10
APC	S1400L
BCORL1	Splice site 178‐1G > T
CD79A	R131fs*61
ERBB2	V842I
ERBB3	G284R ‐ subclonal
KEL	R516 (coding sequence effect C > T)
MSH2	W117 (351G > A), S233fs*13 (697delT)
MSI	High
NF1	R2637(C > T), R1362 (C > T)
PIKC3CA	A1035V
RB1	R358 (C > T)
RET	R330W
TMB	44 mutations/megabase
U2AF1	R198Q
IHC
MMR	dMMR
PD‐L1 TPS	10%

Abbreviations: dMMR, deficient mismatch repair; IHC, immunohistochemistry; MMR, mismatch repair; MSI, microsatellite instability; NGS, next‐generation sequencing; TMB, tumor mutational burden; TPS, tumor proportion score.

Genotyping Results and Interpretation

Genomic analysis of ampullary carcinomas is important for complete characterization as there are genetic differences compared with PDAC as well as differences between the histological subtypes. Although these tumors have not been profiled as extensively, some commonly mutated genes have been identified in ampullary carcinomas. KRAS mutations seem to be common in both histological subtypes, but with lower prevalence than in PDAC [5, 13]. There is also possible enrichment of BRAF mutations in ampullary and periampullary adenocarcinomas [13, 14].

There were no KRAS or BRAF mutations in this tumor, but there was a mutation in ERBB2, another commonly mutated gene in ampullary carcinoma [5]. The V842I substitution in this tumor has been found to occur in high frequency in MSI‐high, BRAF ^WT colorectal cancer, especially in Lynch syndrome [15]. In vitro experiments on the similarly frequent L755S and L720P substitutions show susceptibility to irreversible pan‐HER blockade [15]. Analysis also showed two MSH2 mutations, one of which being MSH2 W117 (351G > A), which is a pathogenic germline mutation associated with Lynch syndrome [16]. IHC showed the PD‐L1 tumor proportion score was 10%, but this is an inconsistent biomarker for response to anti–PD‐1 treatment [17, 18, 19, 20, 21, 22]. The most actionable findings for this patient were MSI‐high status and a TMB of 44 mutations per megabase.

Functional and Clinical Significance

Although MSI‐high is very uncommon in PDAC (≤1%) [6], it is more common in ampullary adenocarcinomas (3%–22%) [7, 8, 9], especially in the context of Lynch syndrome. MSI‐high in ampullary adenocarcinomas provides an opportunity to use PD‐1 and CTLA‐4 inhibitors. TMB is another biomarker that is being investigated as a predictive factor for T‐cell–modulating therapy. The Food and Drug Administration (FDA) has approved pembrolizumab (anti–PD‐1) for treatment of adult and pediatric patients with unresectable or metastatic solid tumors that are TMB‐high (≥10 mutations/megabase) who have progressed after first‐line treatment.

PD‐L1 expression has been well studied and is approved by the FDA as a companion diagnostic treatment for anti–PD‐1 treatment in non‐small cell lung cancer (NSCLC) [17, 22]. However, it is not always an ideal predictive biomarker for immune checkpoint inhibitors as in some tumors, like advanced NSCLC and renal cell carcinoma, no positive correlation between PD‐L1 expression and treatment response has been identified [18, 19]. Additionally, there are instances in which patients have tumors with no or low PD‐L1 expression but still exhibit durable clinical response [20]. Many factors contribute to the shortcomings of PD‐L1 expression as a predictive biomarker. Biopsies represent a small region, and overall PD‐L1 expression may not be represented by the biopsy because of tumoral heterogeneity [21]. Expression of PD‐L1 by tumors can also change over time as expression can be induced by IFN‐γ from a treatment‐induced inflammatory response. Additionally, thresholds for evaluating PD‐L1 expression are lacking, especially in less common tumors, like ampullary adenocarcinoma [17]. Some studies have also found that the cell type on which PD‐L1 is expressed may need to be considered when using PD‐L1 expression to predict response to immune checkpoint inhibitors. Expression of PD‐L1 on tumor‐infiltrating immune cells, in addition to on tumor cells, may be predictive of response [17].

Treatment Strategies

The confirmation of MSI‐high status and high TMB led the interdisciplinary tumor board to recommend T‐cell–modulating immunotherapy at presentation. After FOLFIRINOX administration, owing to insurance restrictions, and subsequent progression, the medical oncologist conducted a peer‐to‐peer discussion with the insurance company to secure approval for combined nivolumab plus ipilimumab with the goal of improved response to enable surgery. This regimen is approved for patients with dMMR or MSI‐high colorectal cancer who have been treated previously with standard chemotherapy drugs. Combined therapy was preferred for this patient as response to nivolumab plus ipilimumab has been shown to be better than nivolumab alone in dMMR/MSI‐high metastatic colorectal cancer (objective response rate 55% vs. 31%) [23]. The goal was to downstage her disease, which had further progressed with chemotherapy, in order to enable surgical resection.

Patient Update

Combined nivolumab (1 mg/kg) and ipilimumab (3 mg/kg) were administered every 3 weeks for four total cycles. The patient experienced uveitis, evaluated by an ophthalmologist and treated with steroid eye drops, and mild pruritus. Her epigastric pain resolved, and her appetite improved dramatically during treatment. Her body weight increased from 69.6 kg to 75.3 kg from cycle 1 to cycle 4. At administration of cycle 2, CEA was 44.23 ng/mL and at cycle 3, CEA was significantly reduced to 3.20 ng/mL.

After cycle 4, abdominal and pelvis CT with contrast revealed a decrease in the size of the mass, which was deemed a partial response. This imaging revealed a 5.2‐cm mass, reduced from 7.5 cm following FOLFIRINOX treatment, with no vascular involvement with respect to superior mesenteric artery, superior mesenteric vein, or portal vein but with abutment of the IVC (Fig. 1B). Based on another discussion with the multidisciplinary tumor board, pancreaticoduodenectomy with possible vascular resection and reconstruction was recommended. Pancreaticoduodenectomy was performed and the patient was discharged after 4 days with no major complications. Pathology demonstrated no residual carcinoma in the primary tumor or in 24 regional lymph nodes. Specimens revealed a complete response with prominent acellular mucin and no viable tumor.

Conclusion

This report highlights a case of periampullary adenocarcinoma in a patient with known Lynch syndrome that exhibited pathological complete response to combined nivolumab plus ipilimumab neoadjuvant therapy. This case exemplifies an instance in which first‐line use of immunotherapy, instead of chemotherapy, may be appropriate. For patients with lymph node or vasculature involvement, surgery without neoadjuvant treatment is not possible. The current neoadjuvant standard of care is chemotherapy, often with a fluorouracil–based regimen. These regimens are not universally effective and are associated with serious side effects. In this case, with an MSI‐high, high mutational burden tumor with elevated PD‐L1 expression in the context of Lynch syndrome, immunotherapy with combined nivolumab and ipilimumab yielded a pathological complete response. There is precedent for first‐line immunotherapy as pembrolizumab was recently approved by the FDA as a first‐line treatment for patients with MSI‐high or dMMR colorectal cancer. Specifically, when the goal of treatment is to facilitate downstage and prolong progression‐free survival, nivolumab plus ipilimumab should be considered, but trials in periampullary adenocarcinomas are required to confirm usage. However, it is increasingly clear that response to immune checkpoint blockade is tumor agnostic. Additionally, biomarker and genetic testing is crucial for ampullary adenocarcinomas as they often harbor mutations or characteristics, different from PDAC, that can be effectively targeted to achieve significant response.

Glossary of Genomic Terms and Nomenclature

dMMR: deficient mismatch repair leads to an increased rate of mutations

Microsatellite instability: short tandem repeats are susceptible to mismatch error that, in the case of dMMR, result in the accumulation of mutations of repeat length alterations

MSH2: the mutS homolog 2 gene encodes for a protein that is involved in DNA repair

Next generation sequencing: high‐throughput sequencing technologies that can be used to target specific regions of the genome

Author Contributions

Conception/design: John Herndon, Samuel J. Ballentine, Kian‐Huat Lim, Ryan C. Fields

Provision of study material or patients: John Herndon, Samuel J. Ballentine, Kian‐Huat Lim, Ryan C. Fields

Collection and/or assembly of data: Vikram Pothuri, John Herndon, Samuel J. Ballentine, Kian‐Huat Lim, Ryan C. Fields

Manuscript writing: Vikram Pothuri, John Herndon, Samuel J. Ballentine, Kian‐Huat Lim, Ryan C. Fields

Final approval of manuscript: Vikram Pothuri, John Herndon, Samuel J. Ballentine, Kian‐Huat Lim, Ryan C. Fields

Disclosures

The authors indicated no financial relationships.