Screening Proves Essential for Addressing High-Risk Pancreatic Cancer

Pancreas | Image credit: © magicmine via Adobe Stock

In a time when cancer research has made breakthroughs in multiple settings, pancreatic cancer has remained a difficult disease to detect and treat adequately, leading to a poor survival rate. As an estimated over 66,000 new cases will be diagnosed and 51,000 patients will die of pancreatic cancer in 2024 oncologists are looking for all means possible to improve outcomes for patients with pancreatic cancer at every level of risk.¹

In patients diagnosed with early-stage disease, better surgical techniques, such as robotic surgery, and less invasive approaches have been implemented successfully. In inoperable disease, oncologists are turning to biomarker-based targeted therapies, making genetic testing important for every patient. Individuals at high risk because of family history and genetic factors can be screened regularly to ensure pancreatic cancer is caught at an early stage.

The inability to diagnose pancreatic cancer early is a major barrier to effective care. “Most pancreatic cancers are asymptomatic in the early stages, and unfortunately, if we don't intervene in the earlier stages, we don't have as many treatment options available,” Suzanne Schiffman, MD, a surgical oncologist at Allegheny Health Network (AHN) and assistant professor at Drexel University School of Medicine, said in an interview with Targeted Oncology.

Importance of Early Diagnosis

Part of the challenge is early detection. Dulabh K. Monga, MD, a medical oncologist at AHN and associate professor at Drexel University School of Medicine, explained in an interview that since the pancreas is a small organ surrounded by other organs, patients may only show symptoms of disease only when the pancreatic duct or bile duct is blocked. By this point, the disease is often advanced and unresectable. Meanwhile, Schiffman pointed out that symptoms such as weight loss, abdominal pain, jaundice, diabetes, and nausea/vomiting are nonspecific, making the process of diagnosis longer and more difficult. Diagnosis can be made with a CT scan or MRI and a tissue biopsy, which can be assisted by endoscopic ultrasound.

“The relative overall survival for all stages is only around 10%. But if we diagnose patients in earlier stages and they're able to undergo surgery [in] stage I, which is considered local disease, the overall survival is about 30% to 40%, which is obviously significantly better,” said Schiffman. She added that when the disease has spread to regional lymph nodes in stage II or III disease, survival drops to 13%. Whereas for stage IV pancreatic cancer, survival drops down to 3%.²

As a surgeon, Schiffman said this can be simplified to operable vs inoperable disease, but borderline resectable disease is an important subgroup where patients can have major benefit from surgery. However, it is more challenging due to the spread of disease into blood vessels, often requiring vascular reconstruction.

She said that resection of pancreatic tumors has benefited from general improvements to anesthesia and pain control, as well as more experience among surgeons in performing the procedures. Additionally, minimally invasive approaches improve the patient’s experience, reduce recovery times and time spent in the hospital, and allow patients to begin adjuvant chemotherapy sooner after resection.

The importance of early intervention in this disease led to AHN’s creation of a High-Risk Pancreatic Cancer Clinic that strives for early detection. The monthly clinic employs regular screening of patients who have high risk of developing pancreatic cancer over the course of their lifetime. Patients can receive a multidisciplinary assessment by a surgical oncologist, gastroenterologist, and a genetic counselor in 1 visit, according to Schiffman. The risk assessment includes personal medical history, medical exam, family history, and a screening plan unique to each individual whose disease is high risk.

Schiffman explained that candidates for the clinic include those with a first-degree relative (parent, sibling, or child) diagnosed with pancreatic cancer at or before the age of 45, 2 or more first-degree relatives diagnosed at any age, or those with 1 first-degree relative and 2 second-degree relatives with malignancies. Those with inherited genetic syndromes such as Lynch syndrome, Peutz-Jeghers syndrome, familial atypical multiple mole melanoma syndrome, gene alterations such as BRCA1/2, PALB2, ATM, or PRSS1 would also be at risk. Patients can also be screened for other associated diseases like breast, ovarian, and prostate cancer.

Detecting disease at the time of pre-cancer high-grade dysplasia brings much better outcomes than advanced disease, making early detection critical, according to Schiffman. She said they are happy to see anyone with a family history who is referred regardless of known genetic mutations.

Optimizing Treatment of Resectable Disease

A successful resection can remove the tumor with clean margins, but recurrence is common and frequently metastatic. According to Schiffman, 70% of recurrences are metastatic, and 30% are local. Chemotherapy has several roles, from downstaging tumors in the perioperative setting to managing micrometastatic disease throughout the body. “We know that we're not doing a patient any good by just removing a tumor locally; we need to treat their whole body and that’s the role that chemotherapy plays,” she said.

Patients with resectable disease commonly receive 4 months of neoadjuvant chemotherapy, plus 2 months of adjuvant therapy following resection, according to Monga. For patients with locally advanced disease, Monga said that 7% to 10% can undergo surgery, if scans show that the patient had a remarkable response to neoadjuvant therapy and encasement of blood vessels is not too severe. She also recommends they receive radiation therapy, particularly if they have negative margins or lymph node involvement.

Recent and Upcoming Targeted Approaches

Over the past few years, improvements to targeted therapy have made next-generation sequencing valuable for all patients, particularly those with advanced disease. Since mismatch repair deficiency makes patients with all solid tumors eligible for immune checkpoint inhibitor therapy, Monga said it is important to test in all patients.

Patients with BRCA1/2 and PALB2 mutations could be candidates for the PARP inhibitor olaparib (Lynparza) based on the POLO trial (NCT02184195).³ Though the trial did not show overall survival benefit, it was a proof of principle for targeted therapy with oral maintenance instead of chemotherapy to improve quality of life for patients. The KRAS G12C mutation, found in 1% to 2% of pancreatic cancers, has been targeted successfully in trials with the inhibitors adagrasib (Krazati) and sotorasib (Lumakras).^4,5

Monga also discussed a trial (NCT03745326) investigating autologous T-cell receptor therapy that successfully targeted mutated KRAS G12D, including in a patient with metastatic pancreatic cancer.⁶ NRG1 fusions were targeted with zenocutuzumab (MCLA-128) in the eNRGy trial (NCT02912949), demonstrating a 34% overall response rate and 9.1-month median duration of response in 71 previously treated patients including a response in 7 of the 19 patients (39%) who had pancreatic cancer.⁷

Additionally, an mRNA vaccine was investigated in a phase 1 trial (NCT04161755); 16 patients with pancreatic ductal adenocarcinoma received atezolizumab (Tecentriq), the autogene cevumeran neoantigen vaccine, and a modified chemotherapy regimen sequentially in the adjuvant setting. At 18 months’ follow-up, those who demonstrated response in the form of observed vaccine-expanded T-cells had not reached a median recurrence-free survival, compared with 13.4 months (P = .003) in those who did not respond.⁸ An ongoing phase 2 trial (IMCODE003 [NCT05968326]) is comparing this regimen with surgery followed by chemotherapy alone.

Guidance for Community Oncologists

With such poor outcomes and uncertain approaches for the majority of patients, Monga and Schiffman advised multidisciplinary consultations and clinical trial participation as often as possible. Beyond that, it is urgent these patients receive comprehensive germline and somatic testing, and their at-risk family members are also considered for testing.

“We want to engage our community physicians…so that they can learn about the new clinical trials that are opening…what are the different nuances in management of these patients, and also understand why we do germline and somatic testing and [how] the efforts that go into doing all this extra testing for patients are worthwhile,” said Monga.

She warned that germline testing is often left out, even in patients treated at large cancer centers. “When patients are first diagnosed with this devastating disease, germline testing is on their back burner…and they want to just get started on treatment.”

Another important step to take early in the treatment process is consulting a palliative care physician, Monga said. This can improve their quality of life and life expectancy and is valuable to do early on considering the rapid progression of many patients’ disease and the stresses on them emotionally.

She also spoke about AHN’s emphasis on fitness through an oncology rehabilitation and exercise program since patients are often sedentary. Even basic exercises can benefit patients in dealing with chemotherapy toxicities such as neuropathy. Additionally, the institution launched a gym program for patients during the course of neoadjuvant chemotherapy leading up to surgery. Structured exercise has been shown to improve outcomes of surgery and chemotherapy.⁹

Schiffman said that she and others at AHN’s multidisciplinary clinic are available to consult with oncologists in the community to guide treatment decisions such as seeing a surgeon and when to switch treatments. They have often coordinated on guiding patients’ treatment while ensuring they can continue to be treated at their local hospital, so patients don’t have to travel further to receive the best possible care.

She urged individuals in the Pittsburgh area at high risk to seek out AHN’s pancreas clinic and oncologists to reach out with challenging cases. “We’re happy to present their patients [cases and] discuss their patients; they're more than welcome to present patient [cases] at our tumor board. Anything we can offer as far as treatment plan and guidance is something we're very happy to do.”

_References:

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_{2. Survival rates for pancreatic cancer. American Cancer Society. Updated January 17, 2024. Accessed January 15, 2024. http://tinyurl.com/5n6en24c}

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_{4. Bekaii-Saab TS, Yaeger R, Spira AI, et al. Adagrasib in advanced solid tumors harboring a KRASG12C mutation. J Clin Oncol. 2023;41(25):4097-4106. doi:10.1200/JCO.23.00434}

_{5. Strickler JH, Satake H, George TJ, et al. Sotorasib in KRAS p.G12C-mutated advanced pancreatic cancer. N Engl J Med. 2023;388(1):33-43. doi:10.1056/NEJMoa2208470}

_{6. Leidner R, Sanjuan Silva N, Huang H, et al. Neoantigen T-Cell receptor gene therapy in pancreatic cancer. N Engl J Med. 2022;386(22):2112-2119. doi:10.1056/NEJMoa2119662}

_{7. Schram AM, Goto K, Kim D, et al. Efficacy and safety of zenocutuzumab, a HER2 x HER3 bispecific antibody, across advanced NRG1 fusion (NRG1+) cancers. J Clin Oncol. 2022;40(suppl_16). doi:10.1200/JCO.2022.40.16_suppl.105}

_{8. Rojas LA, Sethna Z, Soares KC, et al. Personalized RNA neoantigen vaccines stimulate T cells in pancreatic cancer. Nature. 2023;618(7963):144-150. doi:10.1038/s41586-023-06063-y}

_{9. Malveiro C, Correia IR, Cargaleiro C, et al. Effects of exercise training on cancer patients undergoing neoadjuvant treatment: A systematic review. J Sci Med Sport. 2023;26(11):586-592. doi:10.1016/j.jsams.2023.08.178}