Malignant diseases are the main and leading cause of death in Taiwan, contributing to an urgent need of active care for patients with malignant diseases, regardless whether the early- or late-stage of diseases are defined.1–3 Cancer treatment can be simply grouped into two distinguished therapeutic approaches; one is the highly curative therapy applied either by surgery alone and/or radiation therapy with/without neoadjuvant therapy (NAT) or adjuvant therapy under multi-modality guidance; and the other is the palliative therapy or multidisciplinary decision-making with low possibility of curability, based on the characteristics and patterns of diseases at the initial diagnosis.4–9 Except of some specific systemic diseases, patients with an in situ or organ-limited diseases have a better chance to be cured accompanied with a long-term survival after the initial primary curative treatment.2 However, few patients with proposed curable diseases may recur later even though the initial primary active and curative treatment is given, and subsequently die of diseases, suggesting that an accurate and precise evaluation and appropriate and personalized therapeutic plan to those patients with supposedly curable diseases by far-advanced development of new technology or therapeutic strategy is critically important.10,11 All efforts make the diseases with a maximal chance for curability. The article published in the January issue of the Journal of the Chinese Medical Association entitled “The clinicopathological and genetic differences among gastric cancer patients with no recurrence, early recurrence, and late recurrence after curative surgery” attempted to explore this topic, since the authors’ enrolled subjects belonged to complete resection of tumors and all of them received the curable surgery claimed by authors.12

The authors enrolled 473 patients with gastric cancer (GC) undergoing curative surgery to investigated the impact of genetic alterations and clinicopathological features on disease-free survival (DFS) and overall survival (OS) in these GC patients.12 DFS was classified as no recurrence, early recurrence (defined by < 2 years) and late recurrence (defined by ≥ 2 years).12 The authors found that PIK3CA amplifications in diffuse-type GC were associated with early recurrence and ARID1A mutations were frequently found in patients with single-site recurrence, suggesting that targeted therapy and immunotherapy might be helpful for these patients.12 The current article is interesting and worthy of further discussion.

The authors’ aiming to integrate the molecular pathological factors into the conventional clinicopathological factors to establish a new risk-stratification system in the prediction of DFS and OS and in the guidance of adjuvant therapy in the GC patients is worthy of encouragement, although finally, the authors’ efforts may not be successful. None of evaluated molecular pathological parameters, such as microsatellite instability (MSI), Helicobacter pylori (HP), Epstein-Bar virus (EBV), and genetical mutations (PI3K/AKT pathway, TP53, ARID1A, and B-Raf proto-oncogene [BRAF]) were useful in the prediction of DFS and OS, and by contrast, only conventional clinicopathological parameters, such as elder population (≥ 65 years), and pathological N (lymph node) category were involved in the OS.12 Therefore, subgroup analysis was conducted and finally, the authors found the potential role of PIK3CA amplifications and ARID1A mutations may be related to the certain-type outcomes, such as early recurrence as well as single-site recurrence, respectively.12

Recently, technological improvement, the better understanding of tumorigenesis, the continuous innovation of targeted therapy and chemotherapy regimens, the spread of advanced development of surgery and multidisciplinary decision-making have directed patient-tailored strategies, with the aim of improvement of DFS and OS.9 Among them, a better understanding of tumorigenesis, genetic and epigenetic alternations may provide a brand-new therapeutic approach by developing many uniform and targeted or specific agents in the management of cancer patients when cancer treatment has reached to the plateau.2,13–15

Dr Chen’s suggestions12 as targeted therapy and immunotherapy for specific subtypes of GC patients echoed Dr Grothey’s mention15 in 2020, who reported that nothing has changed cancer therapy more in the past 5 to 10 years than the application of immune checkpoint inhibitors, since MSI-H (high)–deficient mismatch repair (dMMR) cancers are sensitive to treatment with immune checkpoint inhibitors, such as programmed death 1 (PD-1) antibodies, with or without adding cytotoxic T-lymphocyte–associated protein 4 (CTLA-4) antibodies with longer durability of response, better safety profile, and improved quality of life associated with immune checkpoint inhibitor treatment compared with chemotherapy making immune checkpoint inhibitors the preferred choice in these MSI-H-dMMR colorectal cancer patients. The aforementioned mention emphasized the importance in using biomarkers (molecular pathology) to identify the specific genetic/epigenetic alternations of cancers to give a uniform therapy, such as targeted therapy or immunotherapy to these cancer patients, which is also claimed by Dr Chen’s group.12

Furthermore, the benefits of targeted therapy and immunotherapy is limited to particular population with specific genetic/epigenetic alternations, and by contrast, its value can be extended to the general population. A recent study 309-KEYNOTE-775 showed that even though proficient MMR (pMMR) endometrial cancer (EC) patients may have taken advantages of progression-free survival (PFS) and OS under the immune checkpoint inhibitors plus multikinase inhibitors (Lenvatinib as an example) treatment than with chemotherapy (6.6 vs 3.8 months; hazard ratio [HR], 0.60; 95% confidence interval [CI], 0.50–0.72 and 17.4 vs 12.0 months; HR, 0.68; 95% CI, 0.56–0.84, respectively).16 All highlight the strength of using a new risk-stratification system integrating molecular aberrations into the conventionally clinicopathologic and image system which may offer a better patient-tailored therapeutic plan.17 Additionally, it is not only associated with a better prognosis but also associated with the decreased therapy-related adverse events.17 All support the rationale of Dr Chen’s effort12 to integrating the molecular pathological factors into the conventional clinicopathological factors to establish a new risk-stratification system in the prediction of DFS and OS in the GC patients.

Unfortunately, the results of Dr Chen’s study12 seemed to be unsatisfactory in the clinical routine practice, even though the authors claimed that potential value of PIK3CA and ARID1A in the specific subgroups. Many confounding factors may significantly influence their results, explaining the reason related to the relative disappointments of Dr Chen’s study.12 The severity of diseases in the enrolled subjects showing a great variability with dramatically different pathological tumor-node-metastases (TNM) stages from early stage (I and II) to advanced stage (III) may be one of the most critical and important confounding factor to explain why their efforts cannot work. In fact, stage is the most important and independent prognostic factor for nearly all solid tumors.2,8 In theory, it is hard to identify any biomarker showing the similar value as stage in the prediction of outcome of the solid tumors. Therefore, it is not surprising to find little assistance of these biomarkers in the prediction of outcomes (DFS, PFS, or OS) of GC patients.

The aforementioned argument has been raised by audience (Drs Li and Chang18) who questioned whether surgery alone can be an adequate strategy in the management of advanced-stage GC patients. Dr Chen’s study12 showed 13.5% (n = 64) of GC patients have been treated with adjuvant chemotherapy; however, the current National Comprehensive Cancer Network© (NCCN) guidelines recommend adjuvant treatment rather than surgery alone in patients with pT3-4 and/or N+ GC.9,18 Only 29% (n = 137) of GC patients did have negative lymph node metastases (N0); and additionally, 29% (n = 138) of GC patients were classified as pT1-2, suggesting the high possibility of risk of undertreatment in Dr Chen’s group.12 Multidisciplinary team or multimodality treatment is encouraged for advanced-stage cancer patients.2,3,8,9 Since to offer a better chance of survival in the advanced-stage cancer patients is always our goal or our dream, although it is far away from the real world, suggesting the presence of a large discrepancy or a big gap between NCCN recommendation and real-world clinical practice.

Finally, similar to many studies in the literature, the main limitation of the current article cannot avoid many confounding factors.19,20 For example, in real-world clinical practice which is unlike to the well-established prospective, randomized clinical trial, it is hard to enroll the subjected with little heterogeneous characteristics; therefore, it is difficult to make a strong conclusion.16 Additionally, retrospectivity in nature may also be a limit. We still highlight the value of Dr Chen’s article,12 since their data are really a reflective in the real world.

ACKNOWLEDGMENTS

This article was supported by grants from the Taiwan Ministry of Science and Technology, Executive Yuan, Taiwan (MOST 110-2314-B-075-016-MY3 and MOST 111-2314-B-075-045), and Taipei Veterans General Hospital (V112C-154 and V112D64-001-MY2-1).

The authors appreciate the support from Female Cancer Foundation, Taipei, Taiwan.

REFERENCES 1. Wang PH, Yang ST, Liu CH. Neoadjuvant therapy (NAT). J Chin Med Assoc 2023;86:133–4. 2. Wang PH, Yang ST, Liu CH, Chang WH, Lee FK, Lee WL. Endometrial cancer: part I. Basic concept. Taiwan J Obstet Gynecol 2022;61:951–9. 3. Chang WH, Lee NR, Wang PH. Multiple micronodular diseases of lung in gynecologic malignancies. Taiwan J Obstet Gynecol 2022;61:578–9. 4. Wang LW, Liu YS, Jiang JK. The effect of mitomycin-C in neoadjuvant concurrent chemoradiotherapy for rectal cancer. J Chin Med Assoc 2022;85:1120–5. 5. Liu CH, Yang ST, Wang PH. Organ- or function-preservation surgery is recommended, but who is a candidate? J Chin Med Assoc 2023;86:3–4. 6. Yang ST, Liu CH, Wang PH. A trend to minimize the radicality of surgery. J Chin Med Assoc 2023;86:131–2. 7. Yang ST, Liu CH, Wang PH. The less invasiveness is and the better quality of life follows: does it fit all early-stage cervical cancer patients? Taiwan J Obstet Gynecol 2022;61:917–8. 8. Su MH, Wu HH, Huang HY, Lee NR, Chang WH, Lin SC, et al. Comparing paclitaxel-platinum with ifosfamide-platinum as the front-line chemotherapy for patients with advanced-stage uterine carcinosarcoma. J Chin Med Assoc 2022;85:204–11. 9. Rosa F, Schena CA, Laterza V, Quero G, Fiorillo C, Strippoli A, et al. The role of surgery in the management of gastric cancer: state of the art. Cancers (Basel) 2022;14:5542. 10. Liu CH, Yang ST, Chao WT, Lin JC, Lee NR, Chang WH, et al. Pretreatment radiologically enlarged lymph nodes as a significant prognostic factor in clinical stage IIB cervical cancer: evidence from a Taiwanese tertiary care center in reaching consensus. Diagnostics (Basel) 2022;12:1230. 11. Wang PH, Liu CH, Yang ST. Risk-stratification system for pre-operative evaluation J Chin Med Assoc 2023;86:259–61. 12. Chen MC, Su HY, Su YH, Huang KH, Fang WL, Lin CW, et al. The clinicopathological and genetic differences among gastric cancer patients with no recurrence, early recurrence, and late recurrence after curative surgery. J Chin Med Assoc 2023;86:55–62. 13. Liu CY, Lin HF, Lai WY, Lin YY, Lin TW, Yang YP, et al. Molecular target therapeutics of EGF-TKI and downstream signaling pathways in non-small cell lung cancers. J Chin Med Assoc 2022;85:409–13. 14. Chung HJ, Chang YH, Huang YH, Lin TP, Wei TC, Lin FJ, et al. Management of metastatic renal cell carcinoma following prior vascular endothelial growth factor-targeted therapy: a real-world retrospective study from Taiwan. J Chin Med Assoc 2022;85:438–42. 15. Grothey A. Pembrolizumab in MSI-H-dMMR advanced colorectal cancer - a new standard of care. N Engl J Med 2020;383:2283–5. 16. Makker V, Colombo N, Casado Herráez A, Santin AD, Colomba E, Miller DS, et al.; Study 309–KEYNOTE-775 Investigators. Lenvatinib plus Pembrolizumab for advanced endometrial cancer. N Engl J Med 2022;386:437–48. 17. Li YT, Yang ST, Wang PH. Molecular pathology and prognosis of endometrial cancer. Taiwan J Obstet Gynecol 2022;61:921–2. 18. Li YT, Chang WH. Is it possible that advanced-stage gastric cancer patients can be cured by surgery alone? J Chin Med Assoc 2023;86:348–9. 19. Hsu PW, Shen YW, Syam S, Liang WM, Wu TN, Hsu JT, et al. Patients with periodontitis are at a higher risk of stroke: a Taiwanese cohort study. J Chin Med Assoc 2022;85:1006–10. 20. Lin CC, Wu MF, Chang YL, Sheu WH, Liou WS. Glycemic control was associated with nonprostate cancer and overall mortalities in diabetic patients with prostate cancer. J Chin Med Assoc 2022;85:331–40.