Exploring the complexities of metachronous primary tumors after surgically managed pancreatic cancer—why lightning strikes twice

Pancreatic ductal adenocarcinoma (PDAC) continues to be a very formidable and aggressive malignancy. Symptoms of PDAC tend to appear in an advanced stage of the disease, which contributes to a late diagnosis and subsequent poor prognosis. For those patients fortunate enough to present with resectable disease, the recurrence rate is quite high. Overall, there is only a 12.8% 5-year relative survival from PDAC (1). After surgical resection, the focus for the survivors is the surveillance and detection of local or distant PDAC recurrence. As the survival rates have slowly increased over the past decade, there are now more PDAC survivors than ever. In this interesting study, Zhang et al. addressed the issue of the increased risk of PDAC survivors to develop additional non-related malignancies. They found that patients who underwent curative pancreatic resection tend to develop secondary tumors at a higher rate than expected for a normal patient population when followed long term. Specifically, they utilized the Surveillance, Epidemiology, and End Results (SEER) database using 6,100 patients, in which 267 (4.4%) developed secondary cancers at a median of 6.2 years follow-up post resection. The most common sites for secondary primary tumor growth were found in the breast, prostate, and lung tissue (2). Metachronous malignancy was observed in the prostate and lungs in a quicker progression (median of 34 and 40.5 months respectively) than that of breast and colorectal cancer (median of 49 and 52.5 months respectively). Zhang et al. emphasized that there was an increased prevalence in men rather than women, those who underwent chemotherapy and radiation, but no statistical significance in patient race, age or site of the pancreatic tumor. While the primary focus of practicing clinicians is to examine for recurrence, Zhang et al. highlighted the importance of screening these patients for secondary tumors in addition to following the standard surveillance guidelines.

This study, however, does not address the cause for increased cancer risk in this patient population. The reason for secondary tumor growth is multifactorial and can possibly be attributed to genetic and behavioral cancer risk factors. Chance or poor luck is likely not a valid explanation for this phenomenon. Similar to lightning striking the same place twice, there is likely an underlying explanation for this repeated occurrence. According to the National Aeronautics and Space Administration (NASA), lightning tends to strike in areas that have already been hit before with a predisposition to locations that draw electrical currents (3) such as air bases, electrical companies with wires underground, etc. This can be analogous to PDAC patients who get a secondary malignancy that may share common risk factors. Common environmental factors include smoking, alcohol use, and obesity among others. Common genetic risk factors may also be in play. Alternative causes of secondary tumor formations are due to recognized or not yet recognized genetic abnormalities such as DNA mismatch repair genes, nonfunctioning tumor-suppressing genes, and other genetic mutations. Each of these predispositions can cause the patient to have an increased risk of developing primary malignancies. For example, patients may be affected with Lynch syndrome, BRCA1/2 mutations, or PALB2, each of which predispose the affected patient to colorectal and breast cancer respectively, along with PDAC (4,5).

Additional explanations may include increased surveillance resulting in detection of incidentally found malignancies. Post-pancreatic cancer diagnosis, patients will have testing and imaging done at intervals and frequencies much greater than the average population. These diagnostic tools include history and physicals, computed tomography (CT) scans, magnetic resonance imaging (MRI)’s, ultrasound, endoscopy, etc. as well as frequent physical examinations. The increased incidental finding of metachronous tumors distant from the pancreas may be simply due to increased observation of patients after pancreatic resection.

Another explanation for secondary tumor growth is treatment related malignancy. Although unlikely, it is well known that chemotherapy and radiation can cause neoplastic tissue changes that may develop malignancy over time. Dracham et al. keyed in on various factors that influence the outcome of patients that undergo radiation therapy, some of which include age at the time of radiation, dose and volume of irradiated areas, as well as type of tissue being radiated. Each of these elements contributes to the late side effects of radiation therapy, especially radiation-induced secondary malignancies. They continued by stating that many chemotherapeutic agents, such as taxanes, lenalidomide, and tamoxifen have been identified as having an increased risk of developing secondary malignancies. Again, while unlikely to be a major factor, this potential contributor to increased incidence cannot be discounted (6).

A final postulated cause of secondary malignancy is immune system suppression due to various reasons such as the treatment, surgery, and recovery from PDAC. Surgery, chemotherapy, radiation, as well as cancer itself may suppress the immune system of the patient, which increases their vulnerability to malignancies. It is becoming increasingly recognized that an intact immune system with active immune surveillance may play a role in preventing or controlling cancer development (7).

This study is novel, interesting, and brings attention to the issue of surveillance for PDAC survivors for other non-related malignancies. It is clear that the majority of patients with pancreatic cancer have a poor prognosis, however, those who receive chemotherapy along with surgical resection have an increased likelihood of reaching the 5-year survival mark. However, there will undoubtedly be patients that reach this timeframe who are affected by secondary tumors distant from the pancreas. While research has primarily been targeted at recurrence regarding PDAC, studies must also be aimed at identifying the risk factors that predispose to secondary malignancy. Immunosuppression, genetic abnormalities, lifestyle risk factors, and treatment related malignancies are all topics that need to be explored further in depth to correlate to tumor formation. Lightning may tend to strike the same patient twice, but with increased surveillance post-pancreatic resection, early recognition and effective treatment may offer yet another chance of cancer cure.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Journal of Gastrointestinal Oncology. The article did not undergo external peer review.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://jgo.amegroups.com/article/view/10.21037/jgo-24-448/coif). J.A.S. serves as an unpaid editorial board member of Journal of Gastrointestinal Oncology from February 2024 to January 2026. The other author has no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

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