ACRT Journal

Figure 2: Diagnostic performance of hPG80 for cancer positive individuals. Receiver operating characteristic curves (ROC) of hPG80 in differentiating cancer positive individuals from cancerfree individuals. AUC: Area under the curve and 95% CI: 95% confidence interval.

Cases Presentation

Patient 1.

A 71-year-old male, healthy and fit, with a 50-year smoking history, consulted our clinic in February 2020. His family history included gastric cancer in his father (deceased at 73) and four siblings diagnosed with cancer: two with leukemia, one with prostate cancer, and one with rectal cancer - all successfully treated and alive at the time being. Based on our risk stratification criteria, he was classified as high-risk for cancer development. His hPG80 level was 21 pM, prompting a comprehensive clinical and laboratory assessment, including a CT scan of the thorax and abdomen. All laboratory results were normal (including PSA 3.9 ng/mL and CEA of 2.1 ng/mL), and his scan of thorax was normal. However, a complex cyst (29 × 21 × 22 mm) with a thick, irregular wall and contrast uptake was detected in his left kidney, classified as a Bosniak type 3 cyst. He was referred to a urology hospital for follow-up imaging, as per guidelines. After 2 years, his cyst was surgically removed.

In April 2024, he developed a persistent cough, leading to a new CT scan, which revealed two separate lung cancers: a squamous cell carcinoma in the right middle lobe (treated with surgery) and an adenocarcinoma in the left upper lobe (treated with curativeintent stereotactic radiation). He subsequently underwent adjuvant chemotherapy and immunotherapy for both tumors. As of now (11 months post-diagnosis), he remains disease-free and has returned to work.

Patient 2.

A 60-year-old male with a medical history of percutaneous coronary intervention (PCI) of the LAD and Cx in 2018, type 2 diabetes, and hypothyroidism (managed with oral antidiabetic drugs and thyroxin) consulted our clinic in February 2020. He was classified as high-risk for cancer due to a long smoking history, although he had stopped smoking 16 years prior and had no first-degree relatives with cancer. His hPG80 level was 11.9 pM, prompting a comprehensive evaluation, including: full clinical and laboratory assessment (all normal and PSA 2.16 ng/mL and CEA of 3.4 ng/ mL), CT scan of the thorax and abdomen and colonoscopy. CT scan showed a small nodule in the right lower lobe, and an 11 mm nodule in the left lower lobe, both initially considered benign postinfectious nodes. The radiologist recommended a follow-up CT in 3 months. The colonoscopy detected seven benign polyps which were subsequently removed. Given his elevated hPG80 level, we referred him to a PET scan, which showed moderate uptake in the left lower lobe nodule. A biopsy was inconclusive, leading to thoracotomy in July 2020. Intraoperative biopsy confirmed a carcinoid tumor, prompting an onsite lobectomy of the left lower lobe. Final histology confirmed a completely resected carcinoid tumor with no lymph node metastases. The patient recovered well and was in good condition 10 weeks post-surgery. Four years later, follow-up at the hospital has shown no recurrence of lung cancer and no signs of other malignancies.

Patient 3.

A 65-year-old female, healthy and never-smoker, consulted our clinic in February 2020. Her mother had been diagnosed with colon cancer at age 78, classifying her as high-risk due to a first-degree relative with cancer. Her hPG80 level was 9.4 pM, prompting further evaluation. Full clinical examination and laboratory tests revealed low hemoglobin levels, positive fecal occult blood (FOB) test, and negative tumour markers including CEA of 1.8 ng/mL. Colonoscopy detected an obstructive tumor in the transverse colon and an adenoma at the anorectal junction. She underwent successful surgery, her tumour was classified as Duke C, followed by adjuvant chemotherapy (FLOX) for 3 months. Follow-up results showed that her hPG80 level dropped below the LoQ. No signs of recurrence or new cancers have been detected after 4 years of observation.

Patient 4.

A 63-year-old male, healthy never-smoker, consulted our clinic in February 2020. His only medical issue was enlarging prostate symptoms for several years, with a normal PSA of 1.2 ng/mL. His family history included one sister, and one daughter diagnosed with breast cancer (both successfully treated with surgery, adjuvant radio/chemotherapy, and no signs of recurrence). Given his two first-degree relatives diagnosed with cancer at a young age, he was categorized as high-risk for cancer development. Initial findings showed an hPG80 level of 3.5 pM (intermediate range). He was advised to repeat hPG80 testing after 12 months. In August 2020, the patient underwent transurethral resection of the prostate (TUR-P) due to worsening lower urinary tract symptoms (LUTS). Preoperative ultrasound showed a normal prostate. PSA level was stable at 1.2 ng/mL. The biopsy showed however an unexpected result: a prostate cancer (Gleason 3+3 = 6). TUR-P was successful, resolving urinary symptoms. Three months post-treatment, PSA decreased to 0.66 ng/mL, hPG80 level fell below the LoQ, indicating biochemical success. Four-year follow-up showed no signs of cancer recurrence. PSA was stable at 0.7 ng/ml and hPG80 remained below LoQ.

Discussion

In this first monocentric real-world data study with a 4-year follow-up, we were able to detect 4 patients with cancers of different origins using hPG80 test that would not have been detected that early using standard procedures. Furthermore, the 16 patients with levels of hPG80 below LoQ were cancer-free 4 years after the initial enrolment. Overall, this observational study yielded a sensitivity of 100%, a specificity of 80%, a Negative Predictive Value (NPV) of 100% and a Positive Predictive Value (PPV) of 50%. Of course, this study has limitations. First the small number of patients enrolled in the study can limit the power of the statistical analysis. Second, this study is a single-centre study that will require external validation to confirm these promising results.

New cancer screening technologies, like the MCED tests, should be carefully evaluated for efficacy and cost, but adding it to current guidelines could be an efficient strategy for high-risk groups (e.g., older adults, smokers) to improve detection of multiple cancer types, including aggressive ones without current screening options [1,2,24-26].

Who should be screened with hPG80 and how often?

Since there are no established studies determining the optimal screening population or interval for hPG80 or similar MCED tests, we can use cancer registry data to refine our recommendations until larger screening studies are conducted. Norway’s Cancer Registry has maintained high quality registration and follow-up of all newly diagnosed cancers for many years. In 2023, 38,094 new cancer cases were recorded, with 17,708 cases (46.4%) in women and 20,386 cases (53.6%) in men [27].

Between 2018 and 2023, the age distribution of cancer incidence revealed that only 7% of all cancers in men occur before age 50. In women, 13.3% of cancers are diagnosed before age 50. After age 50, there is a sharp rise in cancer incidence, particularly in men. In men, 72.9% of all cancers occur between ages 50 and 80. In women, 64.5% of all cancers occur within this age range. Additionally, there has been a notable rise in early-onset cancers, a trend expected to continue in the coming years [27].

Screening recommendations should be based on risk group. The normal-risk group criteria include no prior malignancy, no significant smoking history, no first-degree relatives with cancer diagnosed at a young age. Screening recommendation for this group is to start screening at age 50 and continue until age 80. The hPG80 test should be done every two years (biennial screening). The high-risk group criteria include history of previous malignancy, smoking history (current or former heavy smoker), and first-degree relatives with cancer, particularly if diagnosed at a young age. Screening recommendation for this group is to start screening at age 40. The hPG80 test should be done once a year between age 40 and 50, and further testing after 50 every other year. These recommendations are based on cancer registry data and current understanding of the biology of cancer progression. Future large-scale screening studies will help further refine these guidelines.

hPG80-based screening and follow-up protocols

hPG80 values are classified as follows: elevated above the ULN, intermediate between the LoQ and ULN, low below the LoQ. As clinicians, the use of MCED tests and subsequent follow-up must be assessed from both a clinical benefit and economic feasibility standpoint. Based on years of clinical experience and findings from this observational study, we propose the following screening and follow-up protocols (Table 3).

Table 3: potential algorithm using hPG80.

hPG80 level above ULN (elevated levels - high risk):

We recommend a comprehensive clinical examination focusing on cancer, along with blood tests to detect cancer markers and checks for blood in urine and feces. Additionally, a CT scan of the neck, chest, abdomen and pelvis should be performed. If no abnormalities are found, we suggest a colonoscopy for further evaluation. If any findings are detected, the next steps will depend on the nature of the findings. If no issues are identified, the patient should be clearly informed of their high-risk status for developing cancer and advised to promptly seek medical attention if any cancer-related symptoms arise. We recommend annual follow-up with clinical and laboratory evaluations. At this stage, additional hPG80 testing is not necessary since the patient has already been classified as high-risk. In the event of a cancer diagnosis, hPG80 should be tested for 3 months post-treatment to confirm the biochemical success of the treatment.

-  hPG80 between LoQ and ULN (intermediate levels – moderate risk):

We recommend a comprehensive clinical examination with focus on cancer detection: blood tests including tumour markers, urine and faecal blood tests. If abnormalities are found, further evaluation is conducted accordingly. If no malignancy is detected, repeat hPG80 testing in 12 months. Further follow-up depends on hPG80 progression and patient history. We recommend annual clinical and laboratory examinations with a focus on early malignancy detection.

-  hPG80 below LoQ (low levels – low risk):

A routine clinical examination at the scheduled screening testing is recommended. If no abnormalities are found, no additional testing is required. A new hPG80 test should be repeated every 2 years after age of 50. Since hPG80 does not detect all cancers, patients should be informed of cancer warning signs and advised to seek medical attention if symptoms arise.

These recommendations provide a structured, evidence-based approach to early cancer detection while ensuring efficient use of medical resources.

In our small observational study, the mean age at testing was 58.5 years. According to data from the Norwegian Cancer Registry, the annual risk of a 58-year-old being diagnosed with cancer is 0.075%. However, in our study population, we identified three cancers at the time of hPG80 testing, meaning 12% of our participants were diagnosed with cancer. While these numbers are based on a small sample size and are not statistically significant, we were struck by the unexpectedly high number of cancers detected. Furthermore, our initial plan was to conduct follow-up hPG80 testing for all patients with intermediate levels after 12 months. Unfortunately, this had to be canceled due to the COVID-19 lockdown.

Conclusion

Beyond its well-established role as a potential tumor marker with clinical benefits in cancer monitoring, prognosis, and early relapse detection, we now use hPG80 as an MCED test following the guidelines outlined above. Through this experience, we have learned the importance of closely following patients with high or intermediate hPG80 levels. Integrating hPG80 testing into our existing check-up protocol has significantly enhanced early cancer detection, reinforcing its value as a promising tool in preventive healthcare.

Acknowledgements

The authors would like to thank all patients and their families, the investigators, study nurses, pharmacists, pathologists, and all study teams.

Ethical Consideration

Informed consents were obtained from all subjects.

Conflict of Interests

AP is Chief Scientific Officer of Progastrin Manufacturing.

DJ is senior scientist consultant of Progastrin Manufacturing.

All other authors: No conflict of interest.

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