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Role of microsatellite instability and HER2 positivity in locally advanced esophago-gastric cancer patients treated with peri-operative chemotherapy

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Abstract

Purpose

Neoadjuvant chemotherapy (NAC) significantly improved the prognosis of patients with locally advanced gastric cancer (LAGC). Several biomarkers, including HER2 and MMR/MSI are crucial for treatment decisions in the advanced stage but, currently, no biomarkers can guide the choice of NAC in clinical practice. Our aim was to evaluate the role of MSI and HER2 status on clinical outcomes.

Methods

We retrospectively collected LAGC patients treated with NAC and surgery +/- adjuvant chemotherapy from 2006 to 2018. HER2 and MSI were assessed on endoscopic and surgical samples. Pathologic complete response (pCR) rate, overall survival (OS), and event‐free survival (EFS) were estimated and evaluated for association with downstaging and MSI.

Results

We included 76 patients, 8% were classified as MSI-H, entirely consistent between endoscopic and surgical samples. Six percent of patients were HER2 positive on endoscopic and 4% on surgical samples. Tumor downstaging was observed in 52.5% of cases, with three pCR (5.1%), none in MSI-H cancers. According to MSI status, event-free survival (EFS) and overall survival (OS) were higher for MSI-H patients to MSS [EFS not reached vs 30.0 months, p = 0.08; OS not reached vs 39.6 months, p = 0.10].

Conclusion

Our work confirms the positive prognostic effect of MSI-H in the curative setting of LAGC, not correlated with pathologic tumor downstaging. Prospective ad-hoc trial and tumor molecular profiling are eagerly needed.

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Data availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

References

  1. American Cancer Society. Cancer Facts & Figures 2022. Atlanta, Ga: American Cancer Society; 2022.

    Google Scholar 

  2. Rüdiger Siewert J, Feith M, Werner M, Stein HJ. Adenocarcinoma of the esophagogastric junction: results of surgical therapy based on anatomical/topographic classification in 1,002 consecutive patients. Ann Surg. 2000;232(3):353–61.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Cunningham D, Allum WH, Stenning SP, Thompson JN, Van de Velde CJ, Nicolson M, et al. Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. N Engl J Med. 2006;355(1):11–20.

    Article  CAS  PubMed  Google Scholar 

  4. Al-Batran SE, Homann N, Pauligk C, Goetze TO, Meiler J, Kasper S, et al. Perioperative chemotherapy with fluorouracil plus leucovorin, oxaliplatin, and docetaxel versus fluorouracil or capecitabine plus cisplatin and epirubicin for locally advanced, resectable gastric or gastro-oesophageal junction adenocarcinoma (FLOT4): a randomised, phase 2/3 trial. Lancet. 2019;393(10184):1948–57.

    Article  PubMed  Google Scholar 

  5. Lorenzen S, Thuss-Patience P, Al-Batran SE, Lordick F, Haller B, Schuster T, et al. Impact of pathologic complete response on disease-free survival in patients with esophagogastric adenocarcinoma receiving preoperative docetaxel-based chemotherapy. Ann Oncol. 2013;24(8):2068–73.

    Article  CAS  PubMed  Google Scholar 

  6. Gervaso L, Pellicori S, Cella CA, Bagnardi V, Lordick F, Fazio N. Biomarker evaluation in radically resectable locally advanced gastric cancer treated with neoadjuvant chemotherapy: an evidence reappraisal. Ther Adv Med Oncol. 2021;13:17588359211029559.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Hause RJ, Pritchard CC, Shendure J, Salipante SJ. Classification and characterization of microsatellite instability across 18 cancer types. Nat Med. 2016;22(11):1342–50.

    Article  CAS  PubMed  Google Scholar 

  8. Yamamoto H, Imai K. Microsatellite instability: an update. Arch Toxicol. 2015;89(6):899–921.

    Article  CAS  PubMed  Google Scholar 

  9. McGrail DJ, Garnett J, Yin J, Dai H, Shih DJH, Lam TNA, et al. Proteome instability is a therapeutic vulnerability in mismatch repair-deficient cancer. Cancer Cell. 2020;37(3):371-386.e12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Smyth EC, Wotherspoon A, Peckitt C, Gonzalez D, Hulkki-Wilson S, Eltahir Z, et al. Mismatch repair deficiency, microsatellite instability, and survival: an exploratory analysis of the Medical Research Council Adjuvant Gastric Infusional Chemotherapy (MAGIC) Trial. JAMA Oncol. 2017;3(9):1197–203.

    Article  PubMed  Google Scholar 

  11. Pietrantonio F, Miceli R, Raimondi A, Kim YW, Kang WK, Langley RE, et al. Individual patient data meta-analysis of the value of microsatellite instability as a biomarker in gastric cancer. J Clin Oncol. 2019;37(35):3392–400.

    Article  PubMed  Google Scholar 

  12. André T, Tougeron D, Piessen G, de la Fouchardière C, Louvet C, Adenis A, et al. Neoadjuvant nivolumab plus ipilimumab and adjuvant nivolumab in patients (pts) with localized microsatellite instability-high (MSI)/mismatch repair deficient (dMMR) oeso-gastric adenocarcinoma (OGA): The GERCOR NEONIPIGA phase II. J Clin Oncol. 2022;40(4_suppl):244.

    Article  Google Scholar 

  13. Plum PS, Gebauer F, Krämer M, Alakus H, Berlth F, Chon SH, et al. HER2/neu (ERBB2) expression and gene amplification correlates with better survival in esophageal adenocarcinoma. BMC Cancer. 2019;19(1):38.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Bang YJ, Van Cutsem E, Feyereislova A, Chung HC, Shen L, Sawaki A, et al. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet. 2010;376(9742):687–97.

    Article  CAS  PubMed  Google Scholar 

  15. Stroes CI, van den Ende T, Derks S, van Laarhoven HWM. A systematic review of HER2 blockade for the curative treatment of gastroesophageal adenocarcinoma: Successes achieved and opportunities ahead. Cancer Treat Rev. 2021;99:102249.

    Article  CAS  PubMed  Google Scholar 

  16. Li Z, Gao X, Peng X, May Chen MJ, Li Z, Wei B, et al. Multi-omics characterization of molecular features of gastric cancer correlated with response to neoadjuvant chemotherapy. Sci Adv. 2020;6(9):eaay4211.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Roth AD, Fazio N, Stupp R, Falk S, Bernhard J, Saletti P, et al. Docetaxel, cisplatin, and fluorouracil; docetaxel and cisplatin; and epirubicin, cisplatin, and fluorouracil as systemic treatment for advanced gastric carcinoma: a randomized phase II trial of the Swiss Group for Clinical Cancer Research. J Clin Oncol. 2007;25(22):3217–23.

    Article  CAS  PubMed  Google Scholar 

  18. NCCN Guidelines. Gastric cancer. Version 2.2022.

  19. Sugawara K, Kawaguchi Y, Seto Y, Vauthey JN. Multidisciplinary treatment strategy for locally advanced gastric cancer: A systematic review. Surg Oncol. 2021;38:101599.

    Article  PubMed  Google Scholar 

  20. Houssami N, Macaskill P, von Minckwitz G, Marinovich ML, Mamounas E. Meta-analysis of the association of breast cancer subtype and pathologic complete response to neoadjuvant chemotherapy. Eur J Cancer. 2012;48(18):3342–54.

    Article  CAS  PubMed  Google Scholar 

  21. Maas M, Nelemans PJ, Valentini V, Das P, Rödel C, Kuo LJ, Calvo FA, et al. Long-term outcome in patients with a pathological complete response after chemoradiation for rectal cancer: a pooled analysis of individual patient data. Lancet Oncol. 2010;11(9):835–44.

    Article  PubMed  Google Scholar 

  22. Li Z, Shan F, Wang Y, Zhang Y, Zhang L, Li S, et al. Correlation of pathological complete response with survival after neoadjuvant chemotherapy in gastric or gastroesophageal junction cancer treated with radical surgery: A meta-analysis. PLoS ONE. 2018;13(1):e0189294.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Al-Batran SE, Hofheinz RD, Pauligk C, Kopp HG, Haag GM, Luley KB, et al. Histopathological regression after neoadjuvant docetaxel, oxaliplatin, fluorouracil, and leucovorin versus epirubicin, cisplatin, and fluorouracil or capecitabine in patients with resectable gastric or gastro-oesophageal junction adenocarcinoma (FLOT4-AIO): results from the phase 2 part of a multicentre, open-label, randomised phase 2/3 trial. Lancet Oncol. 2016;17(12):1697–708.

    Article  CAS  PubMed  Google Scholar 

  24. Persiani R, D’Ugo D, Rausei S, Sermoneta D, Barone C, Pozzo C, et al. Prognostic indicators in locally advanced gastric cancer (LAGC) treated with preoperative chemotherapy and D2-gastrectomy. J Surg Oncol. 2005;89(4):227–36 (discussion 237-8).

    Article  PubMed  Google Scholar 

  25. Kaltenmeier C, Althans A, Mascara M, Nassour I, Khan S, Hoehn R, et al. Pathologic complete response following neoadjuvant therapy for gastric adenocarcinoma: a national cancer database analysis on incidence, predictors, and outcomes. Am Surg. 2021;87(7):1145–54.

    Article  PubMed  Google Scholar 

  26. Fazio N, Biffi R, Maibach R, Hayoz S, Thierstein S, Brauchli P, et al. Preoperative versus postoperative docetaxel-cisplatin-fluorouracil (TCF) chemotherapy in locally advanced resectable gastric carcinoma: 10-year follow-up of the SAKK 43/99 phase III trial. Ann Oncol. 2016;27(4):668–73.

    Article  CAS  PubMed  Google Scholar 

  27. Fernandez E, Cacheux W, Frossard JL, Koessler T, Abou M, Moniez M, et al. Exclusive neoadjuvant chemotherapy in locally advanced resectable gastric and gastro-esophageal junction adenocarcinoma. Dig Liver Dis. 2017;49(5):552–6.

    Article  CAS  PubMed  Google Scholar 

  28. Choi YY, Bae JM, An JY, Kwon IG, Cho I, Shin HB, et al. Is microsatellite instability a prognostic marker in gastric cancer? a systematic review with meta-analysis. J Surg Oncol. 2014;110(2):129–35.

    Article  PubMed  Google Scholar 

  29. Polom K, Marano L, Marrelli D, De Luca R, Roviello G, Savelli V, et al. Meta-analysis of microsatellite instability in relation to clinicopathological characteristics and overall survival in gastric cancer. Br J Surg. 2018;105(3):159–67.

    Article  CAS  PubMed  Google Scholar 

  30. Sohn BH, Hwang JE, Jang HJ, Lee HS, Oh SC, Shim JJ, et al. Clinical significance of four molecular subtypes of gastric cancer identified by the cancer genome atlas project. Clin Cancer Res. 2017;23(15):4441–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Nie RC, Chen GM, Yuan SQ, Kim JW, Zhou J, Nie M, et al. Adjuvant chemotherapy for gastric cancer patients with mismatch repair deficiency or microsatellite instability: systematic review and meta-analysis. Ann Surg Oncol. 2021;29(4):2324–31.

    Article  PubMed  Google Scholar 

  32. Cohen R, Taieb J, Fiskum J, Yothers G, Goldberg R, Yoshino T, et al. Microsatellite instability in patients with stage III colon cancer receiving fluoropyrimidine with or without oxaliplatin: an ACCENT pooled analysis of 12 adjuvant trials. J Clin Oncol. 2021;39(6):642–51.

    Article  CAS  PubMed  Google Scholar 

  33. Grosser B, Kohlruss M, Slotta-Huspenina J, Jesinghaus M, Pfarr N, Steiger K, et al. Impact of tumor localization and molecular subtypes on the prognostic and predictive significance of p53 expression in gastric cancer. Cancers (Basel). 2020;12(6):1689.

    Article  CAS  PubMed  Google Scholar 

  34. Network CGAR. Comprehensive molecular characterization of gastric adenocarcinoma. Nature. 2014;513(7517):202–9.

    Article  Google Scholar 

  35. Kim B, Kang SY, Kim D, Heo YJ, Kim KM. PTEN protein loss and loss-of-function mutations in gastric cancers: the relationship with microsatellite instability, EBV, HER2, and PD-L1 expression. Cancers (Basel). 2020;12(7):1724.

    Article  CAS  PubMed  Google Scholar 

  36. Chida K, Kawazoe A, Kawazu M, Suzuki T, Nakamura Y, Nakatsura T, et al. A Low Tumor Mutational Burden and. Clin Cancer Res. 2021;27(13):3714–24.

    Article  CAS  PubMed  Google Scholar 

  37. Haag GM, Czink E, Ahadova A, Schmidt T, Sisic L, Blank S, et al. Prognostic significance of microsatellite-instability in gastric and gastroesophageal junction cancer patients undergoing neoadjuvant chemotherapy. Int J Cancer. 2019;144(7):1697–703.

    Article  CAS  PubMed  Google Scholar 

  38. He WZ, Hu WM, Wang F, Rong YM, Yang L, Xie QK, et al. Comparison of mismatch repair status between primary and matched metastatic sites in patients with colorectal cancer. J Natl Compr Canc Netw. 2019;17(10):1174–83.

    Article  CAS  PubMed  Google Scholar 

  39. Pietrantonio F, Randon G, Romagnoli D, Di Donato S, Benelli M, de Braud F. Biomarker-guided implementation of the old drug temozolomide as a novel treatment option for patients with metastatic colorectal cancer. Cancer Treat Rev. 2020;82:101935.

    Article  CAS  PubMed  Google Scholar 

  40. Bermúdez A, Arranz-Salas I, Mercado S, López-Villodres JA, González V, Ríus F, et al. Her2-Positive and Microsatellite Instability Status in Gastric Cancer-Clinicopathological Implications. Diagnostics (Basel). 2021;11(6):944.

    Article  PubMed  Google Scholar 

  41. Pereira MA, Ramos MFKP, Dias AR, Faraj SF, Ribeiro RRE, de Castria TB, et al. Expression profile of markers for targeted therapy in gastric cancer patients: HER-2, microsatellite instability and PD-L1. Mol Diagn Ther. 2019;23(6):761–71.

    Article  CAS  PubMed  Google Scholar 

  42. Okines AF, Thompson LC, Cunningham D, Wotherspoon A, Reis-Filho JS, Langley RE, et al. Effect of HER2 on prognosis and benefit from peri-operative chemotherapy in early oesophago-gastric adenocarcinoma in the MAGIC trial. Ann Oncol. 2013;24(5):1253–61.

    Article  CAS  PubMed  Google Scholar 

  43. Hsu JT, Chen TC, Tseng JH, Chiu CT, Liu KH, Yeh CN, et al. Impact of HER-2 overexpression/amplification on the prognosis of gastric cancer patients undergoing resection: a single-center study of 1,036 patients. Oncologist. 2011;16(12):1706–13.

    Article  PubMed  PubMed Central  Google Scholar 

  44. Biesma HD, Soeratram TTD, Sikorska K, Caspers IA, van Essen HF, Egthuijsen JMP, et al. Response to neoadjuvant chemotherapy and survival in molecular subtypes of resectable gastric cancer: a post hoc analysis of the D1/D2 and CRITICS trials. Gastric Cancer. 2022;25:640–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We acknowledge patients and their families for the participation in the study.

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Author notes

  1. Chiara A. Cella and Nicola Fazio: co-last author.

Authors and Affiliations

  1. Division of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology, IEO IRCCS, Via Ripamonti 435, Milan, Italy

    Lorenzo Gervaso, Monica Isabel Meneses-Medina, Stefania Pellicori, Chiara Alessandra Cella & Nicola Fazio

  2. Molecular Medicine Department, University of Pavia, Pavia, Italy

    Lorenzo Gervaso

  3. Division of Pathology, European Institute of Oncology IRCCS, Milan, Italy

    Luca Bottiglieri

  4. Department of Hematology and Oncology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico

    Monica Isabel Meneses-Medina

  5. Division of Digestive Surgery, IEO, European Institute of Oncology IRCCS, Milan, Italy

    Roberto Biffi, Uberto Fumagalli Romario & Stefano De Pascale

  6. Department of Statistics and Quantitative Methods, University of Milan-Bicocca, Milan, Italy

    Isabella Sala & Vincenzo Bagnardi

  7. Pathology Unit, European Institute of Oncology IRCCS, Milan, Italy

    Massimo Barberis

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Contributions

Dr. LG designed the study, collected data, interpreted data, and wrote the manuscript. Dr. LB and Dr. MB performed molecular and histologic analysis and revised the content. Dr. MIMM collected data and critically revised the intellectual content. Dr. SP, Dr. CAC, Dr. RB and Dr. UFR and Dr. SDP critically revised the intellectual content. Prof. VB and Dr. IMS performed statistical analysis and critically revised the intellectual content. Dr. NF designed the study, interpreted data, and wrote the manuscript.

Corresponding authors

Correspondence to Lorenzo Gervaso or Nicola Fazio.

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Conflict of interest

The authors state that they have no conflict of interest directly related to this manuscript. Dr. NF reports Personal Financial Interests: advisory Board for MSD, Institutional Financial Interests: Local PI of trials for Astellas, Beigene, Research grants from MSD, Merck and non-financial Interests with ESMO, GI Faculty member.

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The study been approved and authorized by IEO Institutional Ethical Committee, number UID-2401, April, 27sth 2020.

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Gervaso, L., Bottiglieri, L., Meneses-Medina, M.I. et al. Role of microsatellite instability and HER2 positivity in locally advanced esophago-gastric cancer patients treated with peri-operative chemotherapy. Clin Transl Oncol 25, 3287–3295 (2023). https://doi.org/10.1007/s12094-023-03179-5

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