Pancreatic cancer care has evolved significantly from the beginning of the 21st century. Recent NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) recommend universal germline testing.^1,2 Despite these NCCN recommendations, significant challenges in adoption of universal germline testing and referral for genetic counseling for pancreatic adenocarcinoma continue.^2,3 These barriers could be a result of a combination of causes, including, but not limited to, the need for education and awareness, change of referral practices, access and funding for health care, access to comprehensive somatic and germline testing, and fear of genetic testing among patients. In their excellent study, published elsewhere in this issue, Rosso et al⁴ highlight that development of a dedicated hereditary cancer clinic significantly improved referral rates (77%) for germline testing. They also suggest that delay in obtaining results from germline testing and long wait times to get an appointment with a genetic counselor led to disease progression in 36% of cases.

NCCN has recommended tumor gene profiling along with microsatellite instability/mismatch repair in all patients with pancreatic adenocarcinoma that cannot be completely resected to accomplish a cure (ie, metastatic, recurrent, or locally advanced status).¹ NCCN also recommends germline testing and genetic counseling for all patients with pancreatic adenocarcinoma regardless of their familial history. The Know Your Tumor Initiative⁵ showed that personalized matched therapy based on the genetic findings of the patient’s tumor resulted in improved survival in patients with pancreatic adenocarcinoma. Detection of germline mutations has significant therapeutic implications. Patients with germline mutations may benefit with platinum-based therapy instead of non–platinum-based chemotherapeutic regimens. Genetic counseling after germline testing can further help family members be part of surveillance protocols who may be at increased risk of developing pancreatic adenocarcinoma. Current NCCN recommendations, therefore, have significant and wider implications and open the doors for developing a comprehensive cancer control strategy that identifies patients at risk of developing pancreatic carcinoma, developing surveillance strategies around early detection of pancreatic carcinoma, and providing precision therapeutic options to impact survival outcomes.

In their study of 368 patients with pancreatic adenocarcinoma (125 patients before the NCCN Guidelines change recommending referral and 243 patients after the NCCN Guidelines change), Rosso et al⁴ show that by following NCCN recommendations, germline mutation testing increased, and that referral rates for genetic counseling increased to 77% with the establishment of a hereditary cancer clinic at their facility.

The process for somatic and germline mutation begins at diagnosis of pancreatic adenocarcinoma. The tissue-based diagnosis often occurs after endoscopic ultrasound (EUS)–guided fine-needle aspiration or biopsy (FNA/B). In one of the first comprehensive reviews, we had suggested that cytopathologist review of EUS-guided FNA is critical to the success of this procedure and its diagnostic performance. We also predicted that EUS-guided FNA will become the standard of care for diagnosis of pancreatic carcinoma.⁶ Furthermore, we also demonstrated that EUS-guided FNA is highly sensitive (96%) and specific (100%) and provides a high level of diagnostic accuracy (98%) even for small tumors (<2.5 cm), including those from the pancreas.⁷ Identifying and treating early pancreatic adenocarcinomas (<3.0 cm) has a significant impact on survival rates for pancreatic carcinoma. Such morphology-based studies led to a change in the NCCN Guidelines in 2006, and to date EUS-guided tissue acquisition continues to be the gold standard for the diagnosis of pancreatic adenocarcinoma. Our earlier study highlighted that pathologist-performed rapid onsite specimen evaluation (ROSE) helps procure adequate tissue and that biomarker studies can reliably be performed to reduce indeterminate diagnosis for pancreatic malignancies.⁸ In the past 25 years, significant advances have been made and the key role of pathologists in morphologic diagnosis and their involvement in genomic testing has helped improve precision therapeutics for pancreatic adenocarcinoma. Recently, the WHO has also recommended that tumor mutational profiling can be performed on EUS-guided FNA/B and that it can help with diagnostic and therapeutic decision-making.⁹ In a recently published Jhala algorithm, a stepwise process of rapid morphologic assessment of pancreatic FNA is highlighted along with an ever-expanding role of molecular targets for precision therapeutics.¹⁰ In today’s practice, early detection of somatic and germline testing is of critical therapeutic significance. In this setting, establishing a workflow with EUS-guided tissue acquisition with a critical role for pathologist-performed ROSE and tissue triaging for genomic testing at the time of the procedure cannot be overemphasized. This has a solid potential to improve compliance with the NCCN Guidelines.

Other noted attempts to become compliant with NCCN Guidelines to impact patient outcomes have occurred. Other investigators used a strategy to implement in-clinic genetic testing and showed that it can lead to an increase in germline testing from 19% to 71%.¹¹ Another team of investigators used a strategy of generating automated referrals for genetic counseling and multigene germline testing at diagnosis of pancreatic carcinoma. This strategy also led to significant increases in compliance with the NCCN Guidelines for universal germline mutation testing.¹² The key for any strategy to work is to initiate somatic and universal germline testing early at diagnosis. For example, proactively collecting and requesting somatic and germline testing at the EUS procedure with pathologist-performed ROSE could increase testing and compliance for timely genetic counseling. In addition, medical centers investing in establishing in-house molecular testing could significantly reduce the time to perform germline mutational testing. This allows faster turnaround to get results and treatment from their medical oncologists for personalized therapies while waiting for an appointment with genetic counselors. Such a change could also increase enrollment for family members to get tested and be enrolled for surveillance as needed.

Ensuring both greater access and equitable access for all patients for which this ancillary testing is indicated will inevitably require additional health care resources and education.¹³ These additional costs per benefit are substantial, with germline testing previously found to have an incremental cost-effectiveness ratio of $121,924/life-years gained.¹³ These added expenditures would need to be covered, as would education and widespread awareness to raise the need for additional resources.¹³ Choradia et al¹⁴ recently published their analysis on the increase in health care lobbying costs for oncology physician professional organizations and prospective payment system–exempt cancer hospitals. Such advocacy efforts may result in increased investment in health care delivery and will improve patient care.

Thus, to fully realize the potential of precision-based therapy, additional investment at every step, including supporting pathologist-performed ROSE, establishing molecular and genetic laboratory services to perform germline testing, and use of informatics technology to optimize referral patterns are key to patient outcomes. A multipronged approach (Figure 1) will certainly improve genomic testing-based precision therapies, to improve patient outcomes for this highly lethal tumor.

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The hexagon of elements of compliance with the NCCN Guidelines for comprehensive control of pancreatic cancer includes 6 key elements for improving adherence. Each of these elements requires education and resources to fully implement and provide for best patient care.

Abbreviations: EUS, endoscopic ultrasound–guided; ROSE, rapid on-site evaluation.

Citation: Journal of the National Comprehensive Cancer Network 22, 5; 10.6004/jnccn.2024.7050